Maternal administration of bisphenol A alters the microglial profile in the neocortex of mouse weanlings

Bisphenol A (BPA) is known to cause abnormal neurogenesis in the developing neocortex. The mechanisms of BPA toxicity concerning neuroinflammatory-related endpoints are incompletely characterized. To evaluate the microglial morphology and the gene expression of pro-inflammatory cytokines in the newborn neocortex, ICR mice were exposed to BPA 200 μg/kg/d on gestational day 6 through post-partum day 21. Weanlings exposed during prenatal and postnatal period to BPA showed an increased number of amoeboid-type microglia, a microglial differentiation disruption (the M1/M2 microglial ratio), and an abnormal expression of genes encoding pro-inflammatory factors. These findings suggest that the well-known neurodevelopmental toxicity of BPA may be related to an increased microglial activation and neuroinflammation in the neocortex.     

Epidemiological evidence that acetaldehyde plays a significant role in the development of decreased serum folate concentration and elevated mean corpuscular volume in alcohol drinkers

BACKGROUND: Elevated mean corpuscular volume (MCV) is a traditional biological marker for alcohol abuse and alcoholism, but the underlying mechanism is unclear. Three recent epidemiologic studies consistently showed that MCV was elevated by alcohol drinking more markedly among individuals with genetically inactive aldehyde dehydrogenase-2 (ALDH2) (encoded by ALDH2*2 mutant allele) than those with active ALDH2 (encoded by ALDH2*1/2*1 genotype), suggesting that the elevated MCV was etiologically linked to acetaldehyde exposure. The purpose of the present study was to clarify further this relationship by examining the status of folate and vitamin B12. METHODS: The study participants were 159 men who were aged 40 to 69 years and randomly selected from a Japanese rural population. The genetic polymorphism of ALDH2 was determined by PCR-restriction fragment length polymorphism method; data on alcohol drinking and other lifestyles were collected using a structured questionnaire; serum concentrations of folate and vitamin B12 were measured using the protein competitive reaction method, and blood cell counts were measured by routine methods. A multiple linear regression model was used to analyze the data. RESULTS:: The relationship between alcohol drinking and serum folate concentration was significantly different between ALDH2 genotypes, indicating that the reduction of serum folate by alcohol drinking was more marked in men with ALDH2*1/2*2 than those with ALDH2*1/2*1. The relationship between alcohol drinking and elevated MCV was significantly stronger in men with ALDH2*1/2*2 than those with ALDH2*1/2*1 even after adjustment for serum folate and vitamin B12 concentrations. CONCLUSIONS: These findings indicate that acetaldehyde plays a significant role in the development of decreased serum folate concentration and elevated MCV by alcohol drinking.     

Long‐term efficacy of the sodium–glucose cotransporter 2 inhibitor,ipragliflozin, in a case of type A insulin resistance syndrome

Type A insulin resistance (IR) syndrome is a severe IR form caused by insulin receptor (INSR) gene defects. Antidiabetic drugs, including high‐dose insulin and insulin‐sensitizing agents, often fail to control associated hyperglycemia. Therapy with recombinant human insulin‐like growth factor 1 can be more effective, but it is expensive. We report a case of type A IR syndrome with an in‐frame INSR heterozygous deletion (ΔLeu999) that was treated with a combination of conventional therapy and ipragliflozin, a sodium–glucose cotransporter 2 inhibitor. Treatment reduced hemoglobin A1c levels (10.0–7.5%) and induced weight loss (54.4–52.0 kg) within 2 months, and the effects were sustained for >3 years. Sodium–glucose cotransporter 2 inhibitors might be useful to normalize blood glucose in type A IR syndrome by reducing bodyweight and ameliorating glucotoxicity.     

Active oxygen species generated by monocytes and polymorphonuclear cells in Crohn's disease

Chemiluminescence (CL) analysis of monocytes and polymorphonuclear cells (PMNs) was performed on 13 patients with Crohn's disease (CD) and 10 healthy volunteers. The percentages of monocyte populations in mononuclear cells obtained from the patients with CD were greater than those from the healthy volunteers, but the numbers of PMNs were not different between the two groups. The peak level of phorbol myristate acetate (PMA)-induced CL activity generated by diluted whole blood from the patients with CD was more significantly elevated than that from the healthy volunteers, whereas the peak levels of opsonized zymosan-induced CL activity did not differ between the two groups. In monocytes, the peak levels of both PMA- and opsonized zymosan-induced CL activity were significantly higher in the patients with CD than in the healthy volunteers. CL in PMNs, however, showed no significant difference between CD and controls. It is suggested that monocytes of CD have a large capacity to generate active oxygen species. The present study suggests that excessive active oxygen species released by monocytes and perhaps macrophages may play an important role in formation of the intestinal lesions in CD.This work was supported by the Grant of Tokuteishitsukan from the Japanese Ministry of Welfare and Health.     

Altered expression pattern of testican-1 mRNA after brain injury

Testican, a chondroitin/heparan sulfate proteoglycan, is primarily expressed in neurons of the adult and embryonic mouse brain, suggesting its role in normal and/or proliferation and differentiation processes of neurons. However, the role of testican in injured brain remains unclear. In the present study we investigated testican-1 mRNA expression pattern after cryo-injury of the brain. In situ hybridization histochemistry revealed that testican-1 mRNA is induced in the region surrounding the necrotic tissue. Time course study of testican-1 mRNA showed the highest level of signal intensity at 7 days after the injury. To determine which cell types express testican-1 mRNA, we performed in situ hybridization histochemistry combined with immunohistochemistry of several cell markers. Testican-1 mRNA signals were detected in the proximal reactive astrocytes, whereas the distribution pattern of testican-1 mRNA positive cells was different from those of mature oligodendrocytes and activated microglia. In addition, signals for testican-1 mRNA overlapped with those of FGF-2 mRNA, showing that these molecules are coexpressed in reactive astrocytes. These results suggest a possibility that testican-1 plays a permissive role for regenerating axons in reactive astrocytes after injury.     

Bradykinin Stimulates Type II Alveolar Cells to Release Neutrophil and Monocyte Chemotactic Activity and Inflammatory Cytokines

In the present study, we evaluated the potential of bradykinin (BK) to induce the release of neutrophil and monocyte chemotactic activity (NCA and MCA) and cytokines from an alveolar type II epithelial cell line, A549 cells. BK stimulated A549 cells to release NCA and MCA in a dose- and time-dependent manner (P < 0.001). Checkerboard analysis revealed that both NCA and MCA involved chemotactic and chemokinetic activity. Molecular sieve column chromatography showed three molecular weight masses (near 19 kd, 8 kd, and 400 d) for NCA and several molecular weight peaks (near 66 kd, 25 kd, 19 kd, 16 kd, and 400 d) for MCA. The release of NCA and MCA was inhibited by cycloheximide and lipoxygenase inhibitors (P < 0.01). The NCA and MCA were inhibited by leukotriene B4 (LTB4) receptor antagonist (P < 0.01), and the concentration of LTB4 was high enough for NCA and MCA. Antibodies to interleukin (IL)-8 and granulocyte colony-stimulating factor (G-CSF) attenuated NCA (P < 0.01), and antibodies to monocyte chemotactic protein-1 (MCP-1), G-CSF, and transforming growth factor (TGF)-β attenuated MCA (P < 0.01). The levels of IL-8, G-CSF, MCP-1, and TGF-β increased time dependently (P < 0.01). BK also stimulated the release of ILeukin-6 from A549 cells (P < 0.001). The receptors responsible for the release of NCA, MCA, and individual chemokines involved both BKB1 and BKB2 receptors. These data suggest that BK may stimulate alveolar type II pneumocytes to release inflammatory cytokines, which then may modulate the lung inflammation.