A review of toxicity studies on graphene-based nanomaterials in laboratory animals

We summarized the findings of toxicity studies on graphene-based nanomaterials (GNMs) in laboratory mammals. The inhalation of graphene (GP) and graphene oxide (GO) induced only minimal pulmonary toxicity. Bolus airway exposure to GP and GO caused acute and subacute pulmonary inflammation. Large-sized GO (L-GO) was more toxic than small-sized GO (S-GO). Intratracheally administered GP passed through the air-blood barrier into the blood and intravenous GO distributed mainly in the lungs, liver, and spleen. S-GO and L-GO mainly accumulated in the liver and lungs, respectively. Limited information showed the potential behavioral, reproductive, and developmental toxicity and genotoxicity of GNMs. There are indications that oxidative stress and inflammation may be involved in the toxicity of GNMs. The surface reactivity, size, and dispersion status of GNMs play an important role in the induction of toxicity and biodistribution of GNMs. Although this review paper provides initial information on the potential toxicity of GNMs, data are still very limited, especially when taking into account the many different types of GNMs and their potential modifications. To fill the data gap, further studies should be performed using laboratory mammals exposed using the route and dose anticipated for human exposure scenarios.     

Oral toxicological studies of black soybean (Glycine max) hull extract: Acute studies in rats and mice, and chronic studies in mice

Black soybean (Glycine max) has been used for traditional medicine and food in Asian countries, but safety of its hull has not been studied. We conducted acute and chronic oral toxicity studies. For the acute study, an extract of black soybean hull (BE; 2.5 g/kg body weight) was administered singly by intragastric intubation to Sprague–Dawley rats and C57BL/6 mice. There was no death or significant decrease in body weight in rats and mice, and the oral LD₅₀ of BE was >2.5 g/kg body weight. In the chronic study, BE was administered at dietary levels of 0% (control), 2.0%, and 5.0% to male and female C57BL/6 mice for 26 weeks. No mortality or toxicologically significant clinical changes were observed through the experimental period. Although body weights, as well as abdominal fat, blood levels of triglyceride and total cholesterol in 5.0% males were significantly lower than that in control and 2.0% groups, these changes were considered not to be adverse. Hematology and histopathological observation revealed no toxicologically significant changes. The no-observed adverse-effect-level of BE was estimated to be 5.0% in the diet (5074.1 mg/kg body weight/day for males and 7617.9 mg/kg body weight/day for females).     

Silk-elastinlike protein polymers for matrix-mediated cancer gene therapy

Silk-elastinlike protein polymers (SELPs) are recombinant polymers designed from silk fibroin and mammalian elastin amino acid repeats. These are versatile materials that have been examined as controlled release systems for intratumoral gene delivery. SELP hydrogels comprise monodisperse and tunable polymers that have the capability to control and localize the release and expression of plasmid DNA and viruses. This article reviews recent developments in the synthesis and characterization of SELP hydrogels and their use for matrix-mediated gene delivery.     

Angiotensin AT2 receptor activates the cyclic-AMP signaling pathway in eel

A unique angiotensin type 2 receptor (AT2) that induces a cAMP signaling pathway was cloned and characterized for the first time in fish, Anguilla japonica. Phylogeny and synteny results showed that the AT2s among fishes and tetrapods share the same origin despite a sub-cluster formation among eel, salmon, and zebrafish. The eel AT2 was expressed abundantly in the spleen and localized at straight arterioles and ellipsoid regions prior to the sinusoid, suggesting a role in the regulation of microcirculation and/or immune response. Various angiotensin (Ang) peptides, including Ang II, Ang III, and Ang IV, were detected in the spleen by a radioimmunoassay coupled with HPLC separation, and these endogenous peptides stimulated a cAMP signaling, which has no crosstalk with cGMP pathway. The common and contrasting features of AT2 between fishes and mammals imply some ancestral characters of AT2, which are important information for receptor binding and evolutionary studies.     

The role of cyclooxygenase-2-dependent signaling via cyclic AMP response element activation on aromatase up-regulation by o,p′-DDT in human breast cancer cells

o,p′-Dichlorodiphenyltrichloroethane (o,p′-DDT) is a DDT isomer and xenoestrogen that can induce inflammation and cancer. However, the effect of o,p′-DDT on aromatase is unclear. Thus, we investigated the effects of o,p′-DDT on aromatase expression in human breast cancer cells. We also examined whether cyclooxygenase-2 (COX-2) is involved in o,p′-DDT-mediated aromatase expression. Treatment with o,p′-DDT-induced aromatase protein expression in MCF-7 and MDA-MB-231 human breast cancer cells; enhancing aromatase gene expression, and enzyme and promoter activity. Treatment with ICI 182.780, a estrogen receptor antagonist, did not affect the inductive effects of o,p′-DDT on aromatase expression. In addition, o,p′-DDT increased COX-2 protein levels markedly, increased COX-2 mRNA expression and promoter activity, enhanced the production of prostaglandin E₂ (PGE₂), induced cyclic AMP response element (CRE) activation, and cAMP levels and binding of CREB. o,p′-DDT also increased the phosphorylation of PKA, Akt, ERK, and JNK in their signaling pathways in MCF-7 and MDA-MB-231 cells. Finally, o,p′-DDT induction of aromatase was inhibited by various inhibitors [COX-2 (by NS-398), PKA (H-89), PI3-K/Akt (LY 294002), EP2 (AH6809), and EP4 receptor (AH23848)]. Together, these results suggest that o,p′-DDT increases aromatase, and that o,p′-DDT-induced aromatase is correlated with COX-2 up-regulation, mediated via the CRE activation and PKA and PI3-kinase/Akt signaling pathways in breast cancer cells.     

Eating ourselves to death (and despair): The contribution of adiposity and inflammation to depression

Obesity and related metabolic conditions are of epidemic proportions in most of the world, affecting both adults and children. The accumulation of lipids in the body in the form of white adipose tissue in the abdomen is now known to activate innate immune mechanisms. Lipid accumulation causes adipocytes to directly secrete the cytokines interleukin (IL) 6 and tumor necrosis factor α (TNFα), but also monocyte chemoattractant protein 1 (MCP-1), which results in the accumulation of leukocytes in fat tissue. This sets up a chronic inflammatory state which is known to mediate the association between obesity and conditions such as cardiovascular disease, type 2 diabetes, and cancer. There is also a substantial literature linking inflammation with risk for depression. This includes the observations that: (1) people with inflammatory diseases such as multiple sclerosis, cardiovascular disease, and psoriasis have elevated rates of depression; (2) many people administered inflammatory cytokines such as interferon α develop depression that is indistinguishable from depression in non-medically ill populations; (3) a significant proportion of depressed persons show upregulation of inflammatory factors such as IL-6, C-reactive protein, and TNFα; (4) inflammatory cytokines can interact with virtually every pathophysiologic domain relevant to depression, including neurotransmitter metabolism, neuroendocrine function, and synaptic plasticity. While many factors may contribute to the association between inflammatory mediators and depression, we hypothesize that increased adiposity may be one causal pathway. Mediational analysis suggests a bi-directional association between adiposity and depression, with inflammation possibly playing an intermediary role.     

Hepatic stellate cells do not derive from the neural crest

BACKGROUND/AIMS: Hepatic stellate cells (HSC) have been hypothesised to derive from the neural crest, based on their expression of multiple neural/neuroendocrine features and their contacts with autonomic nerve endings. METHODS: We studied the emergence of HSC in the liver during embryonic development in a transgenic mouse line expressing yellow fluorescent protein (YFP) in all neural crest cells and their derivatives. Cellular YFP expression in these mice was compared with desmin expression between embryonic day (E) 11.5 and adulthood. RESULTS: YFP was abundantly expressed in neural crest cells delaminating from the neural tube and in all known neural crest-derived structures and cell populations. In particular, YFP expressing cells perfectly mimicked the spatial and temporal pattern of enteric nervous system development from neural crest cells migrating from the postotic region. Cells within the adrenal medulla were also YFP positive. Analysis of the liver showed that desmin-expressing, stellate-shaped, perisinusoidally located HSC were evident from E11.5 onwards. However, no detectable YFP expression was seen in the developing liver or in HSC, from E11.5 until adulthood. CONCLUSIONS: These findings suggest HSC do not descend from the neural crest, and therefore may derive from the septum transversum mesenchyme, from endoderm or from the mesothelial liver capsule.