大鼠产前手机辐射对子代小脑白质的影响

目的:探讨大鼠产前850～1 900 MHz手机辐射对成年子代小脑白质的影响。方法:孕鼠随机分为短时产前手机辐射组、长时产前手机辐射组和对照组,短时和长时辐射组于孕期第1～17日分别进行每天6 h和24 h手机辐射,各组雄性子代大鼠(n＝8)于3月龄取小脑组织,进行苏木精-伊红(HE)染色观察小脑皮质细胞形态,免疫组化和Western blot检测髓鞘碱性蛋白(MBP)、神经微丝-L(NF-L)和胶质纤维酸性蛋白(GFAP)表达。结果:与对照组比较,短时程和长时程产前手机辐射组子代大鼠小脑浦肯野细胞出现形态学改变;与对照组比较,长时程辐射组MBP、NF-L表达明显减少(P均＜0.05),而GFAP表达明显增多(P＜0.05);与短时程辐射组比较,长时程组子代大鼠小脑MBP、NF-L表达明显减少(P均＜0.05),而GFAP表达明显增多(P＜0.05)。结论:产前手机辐射会导致雄性子代大鼠小脑髓鞘和轴突的损害,以及星形胶质细胞的活化,且这种改变与产前手机辐射的时程相关。     

In utero transplantation of neural stem cells ameliorates maternal inflammation-induced prenatal white matter injury

Prenatal white matter injury is a serious problem due to maternal inflammation leading to postnatal disabilities. In this study, we used the periventricular leukomalacia (PVL) model as a common prenatal white matter injury by maternal administration of lipopolysaccharide (LPS). Neural stem cells (NSCs) have shown therapeutic ability in neurological disorders through a different mechanism such as immunomodulation. Here, we studied the preventive potential of NSCs following in utero transplantation into the embryonic lateral ventricle in an LPS-induced white matter injury model. Pregnant animals were divided into three groups and received phosphate buffered saline, LPS, or LPS + NSCs. The brains of offspring were obtained and evaluated by real-time polymerase chain reaction (PCR), immunohistochemy, enzyme-linked immunosorbent assay (ELISA), terminal deoxynucleotidyl transferase-mediated biotinylated-dUTP nick-end labeling (TUNEL), and caspase-3 activity assay. The LPS-induced maternal inflammation degenerated the myelin sheath in the offspring periventricular region which was associated with an increased microglial number, oligodendrocytes degeneration, proinflammatory cytokine secretion, and cell apoptosis. The transplanted NSCs homed into the brain and ameliorated the evaluated parameters. The expression of proinflammatory cytokines interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α), cell apoptosis and caspase-3 activity were inhibited by NSCs. In addition, Olig2 and myelin basic protein immunohistochemy staining showed that prenatal NSCs transplantation augmented the myelination in the periventricular white matter of offspring. In conclusion, we think that prenatal therapeutic strategies, such as in utero NSCs transplantation, may prevent prenatal white matter injury after birth.     

Morphometric Analysis of Normal, Mutant, and Transgenic CNS: Correlation of Myelin Basic Protein Expression to Myelinogenesis

The neurological mutant mice shiverer (shi) and myelin deficient (shimld) lack a functional gene for the myelin basic proteins (MBP), have virtually no myelin in their CNS, shiver, seize, and die early. Mutant mice homozygous for an MBP transgene have MBP mRNA and MBP in net amounts approximately 25% of normal, have compact myelin, do not shiver or seize, and live normal life spans. We bred mice with various combinations of the normal, transgenic, shi, and shimld genes to produce mice that expressed MBP mRNA at levels of 0, 5, 12.5, 17.5, 50, 62.5, and 100% of normal. The CNS of these mice were analyzed for MBP content, tissue localization of MBP, degree of myelination, axon size, and myelin thickness. MBP protein content correlated with predicted MBP gene expression. Immunocytochemical staining localized MBP to white matter in normal and transgenic shi mice with an intensity of staining comparable to the degree of MBP gene expression. An increase in the percentage of myelinated axons and the thickness of myelin correlated with increased gene expression up to 50% of normal. The percentage of myelinated axons and myelin thickness remained constant at expression levels greater than 50%. The presence of axons loosely wrapped with oligodendrocytic membrane in mice expressing lower amounts of MBP mRNA and protein suggested that the oligodendroglia produced sufficient MBP to elicit axon wrapping but not enough to form compact myelin. Mean axon circumference of myelinated axons was greater than axon circumference of unmyelinated axons at each level of gene expression, further evidence that oligodendroglial cells preferentially myelinate axons of larger caliber.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mouse Models of Periventricular Leukomalacia

We describe a protocol for establishing mouse models of periventricular leukomalacia (PVL). PVL is the predominant form of brain injury in premature infants and the most common antecedent of cerebral palsy. PVL is characterized by periventricular white matter damage with prominent oligodendroglial injury. Hypoxia/ischemia with or without systemic infection/inflammation are the primary causes of PVL. We use P6 mice to create models of neonatal brain injury by the induction of hypoxia/ischemia with or without systemic infection/inflammation with unilateral carotid ligation followed by exposure to hypoxia with or without injection of the endotoxin lipopolysaccharide (LPS). Immunohistochemistry of myelin basic protein (MBP) or O1 and electron microscopic examination show prominent myelin loss in cerebral white matter with additional damage to the hippocampus and thalamus. Establishment of mouse models of PVL will greatly facilitate the study of disease pathogenesis using available transgenic mouse strains, conduction of drug trials in a relatively high throughput manner to identify candidate therapeutic agents, and testing of stem cell transplantation using immunodeficiency mouse strains.     

PACAP and VIP increase the expression of myelin-related proteins in rat schwannoma cells: Involvement of PAC1/VPAC2 receptor-mediated activation of PI3K/Akt signaling pathways

PACAP and its cognate peptide VIP participate in various biological functions, including myelin maturation and synthesis. However, defining whether these peptides affect peripheral expression of myelin proteins still remains unanswered. To address this issue, we assessed whether PACAP or VIP contribute to regulate the expression of three myelin proteins (MAG, MBP and MPZ, respectively) using the rat schwannoma cell line (RT4-P6D2T), a well-established model to study myelin gene expression. In addition, we endeavored to partly unravel the underlying molecular mechanisms involved. Expression of myelin-specific proteins was assessed in cells grown either in normal serum (10% FBS) or serum starved and treated with or without 100 nM PACAP or VIP. Furthermore, through pharmacological approach using the PACAP/VIP receptor antagonist (PACAP6-38) or specific pathway (MAPK or PI3K) inhibitors we defined the relative contribution of receptors and/or signaling pathways on the expression of myelin proteins. Our data show that serum starvation (24 h) significantly increased both MAG, MBP and MPZ expression. Concurrently, we observed increased expression of endogenous PACAP and related receptors. Treatment with PACAP or VIP further exacerbated starvation-induced expression of myelin markers, suggesting that serum withdrawal might sensitize cells to peptide activity. Stimulation with either peptides increased phosphorylation of Akt at Ser473 residue but had no effect on phosphorylated Erk-1/2. PACAP6-38 (10 μM) impeded starvation- or peptide-induced expression of myelin markers. Similar effects were obtained after pretreatment with the PI3K inhibitor (wortmannin, 10 μM) but not the MAPKK inhibitor (PD98059, 50 μM). Together, the present finding corroborate the hypothesis that PACAP and VIP might contribute to the myelinating process preferentially via the canonical PI3K/Akt signaling pathway, providing the basis for future studies on the role of these peptides in demyelinating diseases.     

Resveratrol treatment improves the altered metabolism and related dysbiosis of gut programed by prenatal high-fat diet and postnatal high-fat diet exposure

A maternal high-fat (HF) diet sensitizes offspring to the adverse effects of postnatal HF intake and can lead to metabolic dysregulation. Resveratrol, a natural polyphenolic compound found in grapes and red wine, could help to relieve metabolic syndrome dysregulation. Since the gut microbiota is known to be closely related to metabolic homeostasis, this study aimed to investigate the impact of a combination of maternal and postweaning HF diets on the gut microbiota and whether resveratrol could relieve the gut dysbiosis associated with metabolic dysregulation. Sprague–Dawley dams were sustained on either a chow or HF diet before mating, during pregnancy and during lactation. Their offspring were randomly fed chow or a HF diet after weaning. Four experimental groups were generated: CC (maternal/postnatal chow diet), HC (maternal HF/postnatal chow diet), CH (maternal chow/postnatal high-fat diet) and HH (maternal/postnatal HF diet). A fifth group consisted of HH with resveratrol treatment. We found that both maternal and postnatal HF exposure has a distinct effect on the gut microbiota metagenome of offspring. Maternal HF diet exposure decreased plasma acetate, propionate and butyrate level, while postnatal HF diet exposure decreased plasma acetate level in adult life. The metabolic dysregulation programed by the maternal and postnatal HF diets was related to the relevant gut microbiota. Resveratrol treatment ameliorated the altered plasma propionate level related to maternal HF and postnatal HF diet treatment. Resveratrol treatment also improved most of the altered metabolic dysregulation and related dysbiosis programmed by maternal and postnatal HF diet exposure.     

Maternal obesity programmes offspring development of non-alcoholic fatty pancreas disease

Background and aims

The prevalence of pancreatic adenocarcinoma (PAC) parallels rising rates of obesity and dysmetabolism, a possible link being non-alcoholic fatty pancreas disease (NAFPD). We have recently shown that maternal obesity programmes the development of a dysmetabolic and fatty liver (non-alcoholic fatty liver disease, NAFLD) phenotype in adult offspring. Since the pancreas and liver originate from the same embryonic bud, it is plausible that maternal obesity may similarly programme the development of NAFPD. Our objective was to determine the effect of maternal obesity on development of NAFPD in offspring and ascertain contributions of the intra/extra-uterine periods.

Methods

Female C57BL/6J mice were fed either a standard chow (3% fat, 7% sugar) or a hypercalorific diet (16% fat, 33% sugar) for six weeks prior to mating and throughout pregnancy and lactation. Female offspring were cross-fostered for suckling to dams on the same or opposite diet to yield four groups: offspring of lean suckled by lean dams (n = 6), offspring of obese suckled by obese dams (n = 6), offspring of lean suckled by obese dams (n = 5) and offspring of obese suckled by lean dams (n = 6). All offspring were weaned onto a standard chow diet at 21 days and sacrificed at 3 months post-partum for tissue collection.

Results

Offspring subjected to an adverse suckling environment showed significant increases in body weight, pancreatic triglyceride content, TGF-β, collagen gene expression and SBP at rest along with an enhanced restraint stress response, indicating a dysmetabolic and NAFPD phenotype.

Conclusions

Developmental programming is involved in the pathogenesis of NAFPD and appears to be largely dependent on an adverse extra-uterine environment.     

Glucocorticoids decrease serum adiponectin level and WAT adiponectin mRNA expression in rats

Objective

Accumulating evidence suggests that adiponectin plays an important role in the genesis of obesity and insulin resistance. Although it has been shown that glucocortocoids (GC) inhibit adiponectin expression in vitro, there exist discrepant results in vivo. In this study, we observe the effect of GC on the serum adiponectin level and adiponectin expression in white adipose tissue (WAT) in male SD rats.

Methods

An obese rat model was made by a high-fat diet. Both non-obese and obese rats were randomly divided into normal saline (intraperitoneal injection with normal saline 0.2 ml/100 g day for 20 days, NS), a low dose GC group (intraperitoneal injection with hydrocortisone sodium succinate 5 mg/kg day for 20 days, LDG) and a high dose GC group, respectively (intraperitoneal injection with hydrocortisone sodium succinate 15 mg/kg day for 20 days, HDG). Serum adiponectin levels were detected by ELISA and the adiponectin mRNA level was assayed by Northern blot.

Results

The serum adiponectin level significantly decreased after 80 days of the high-fat diet (P < 0.05), while it was not decreased after 80 days of the chow diet (P > 0.05). The serum adioponectin levels in both the non-obese and obese rats were significantly decreased after a 20-day GC injection period (P < 0.01). The adiponectin mRNA levels in epididymal fat after high dose GC injection, in both non-obese and obese rats were also decreased (P < 0.001).

Conclusions

A high-fat diet decreased serum adiponectin levels in the rat. GC decreased serum adiponectin levels, and this might be due to inhibited adiponectin mRNA expression in WAT. High-fat diet and GC have a synergistic effect on inhibiting adiponectin expression in rats.     

Soluble and bound acid protease activity of myelin from bovine cerebral white matter and spinal cord

Isolated myelin of bovine spinal cord was found to degrade exogenous myelin basic protein (MBP) at pH 4.4. Electrophoretic peptide patterns were consistent with limited proteolysis of MBP. Some of the proteolytic activity was soluble at increased ionic strength, some remained bound, withstanding extraction at 37°C for up to 12 hr. While being measurable with exogenous MBP, bound protease degraded neither bound MBP nor any other major intrinsic myelin protein. Both soluble and bound protease activity was completely inhibited by pepstatin A. The patterns of limited proteolysis of MBP they produced were identical. Myelin of cerebral white matter also exhibited soluble and bound acid protease activity which was likewise inhibited by pepstatin A. Protease activity of spinal cord and cerebral myelin is therefore suggested to be due to a cathepsin D-like endopeptidase, present in a loosely and tightly bound form. Both forms increased by 50 to 80% in activity when myelin was isolated from mixtures of white and cortical gray matter. While increased soluble activity of myelin is consistent with binding of cathepsin D of lysosomal origin during the isolation of myelin the tightly bound form might point to a principal mechanism through which exogenous proteins may become attached to the myelin sheath in vivo.     

Maternal High Fat Diet Affects Offspring’s Vitamin K-Dependent Proteins Expression Levels

Studies suggest bone growth & development and susceptibility to vascular disease in later life are influenced by maternal nutrition, during intrauterine and early postnatal life. There is evidence for a role of vitamin K-dependent proteins (VKDPs) including Osteocalcin, Matrix-gla protein, Periostin, and Gas6, in bone and vascular development. This study extends the analysis of VKDPs previously conducted in 6 week old offspring, into offspring of 30 weeks of age, to assess the longer term effects of a maternal and postnatal high fat (HF) diet on VKDP expression. Overall a HF maternal diet and offspring diet exacerbated the bone changes observed. Sex specific and tissue specific differences were observed in VKDP expression for both aorta and femoral tissues. In addition, significant correlations were observed between femoral OCN, Periostin Gas6, and Vkor expression levels and measures of femoral bone structure. Furthermore, MGP, OCN, Ggcx and Vkor expression levels correlated to mass and fat volume, in both sexes. In summary the current study has highlighted the importance of the long-term effects of maternal nutrition on offspring bone development and the correlation of VKDPs to bone structure.     

Synergistic effects of prenatal hypoxia and postnatal high-fat diet in the development of cardiovascular pathology in young rats

We have previously shown that adult offspring exposed to a prenatal hypoxic insult leading to intrauterine growth restriction (IUGR) are more susceptible to cardiovascular pathologies. Our objectives were to evaluate the interaction between hypoxia-induced IUGR and postnatal diet in the early development of cardiovascular pathologies. Furthermore, we sought to determine whether the postnatal administration of resveratrol could prevent the development of cardiovascular disorders associated with hypoxia-induced IUGR. On day 15 of pregnancy, Sprague-Dawley rats were randomly assigned to hypoxia (11.5% oxygen), to induce IUGR, or normal oxygen (control) groups. For study A, male offspring (3 wk of age) were randomly assigned a low-fat (LF, <10% fat) or a high-fat (HF, 45% fat) diet. For study B, offspring were randomized to either HF or HF+resveratrol diets. After 9 wk, cardiac and vascular functions were evaluated. Prenatal hypoxia and HF diet were associated with an increased myocardial susceptibility to ischemia. Blood pressure, in vivo cardiac function, and ex vivo vascular function were not different among experimental groups; however, hypoxia-induced IUGR offspring had lower resting heart rates. Our results suggest that prenatal insults can enhance the susceptibility to a second hit such as myocardial ischemia, and that this phenomenon is exacerbated, in the early stages of life by nutritional stressors such as a HF diet. Supplementing HF diets with resveratrol improved cardiac tolerance to ischemia in offspring born IUGR but not in controls. Thus we conclude that the additive effect of prenatal (hypoxia-induced IUGR) and postnatal (HF diet) factors can lead to the earlier development of cardiovascular pathology in rats, and postnatal resveratrol supplementation prevented the deleterious cardiovascular effects of HF diet in offspring exposed to prenatal hypoxia.     

Divalent cations induce a compaction of intrinsically disordered myelin basic protein

Central nervous system myelin is a dynamic entity arising from membrane processes extended from oligodendrocytes, which form a tightly-wrapped multilamellar structure around neurons. In mature myelin, the predominant splice isoform of classic MBP is 18.5 kDa. In solution, MBP is an extended, intrinsically disordered protein with a large effective protein surface for myriad interactions, and possesses transient and/or induced ordered secondary structure elements for molecular association or recognition. Here, we show by nanopore analysis that the divalent cations copper and zinc induce a compaction of the extended protein in vitro, suggestive of a tertiary conformation that may reflect its arrangement in myelin.     

Role of maternal tissue in the synthesis of polyunsaturated fatty acids in response to a lipid-deficient diet during pregnancy and lactation in rats

During pregnancy and lactation, metabolic adaptations involve changes in expression of desaturases and elongases (Elovl2 and Elovl5) in the mammary gland and liver for the synthesis of long-chain polyunsaturated fatty acids (LC-PUFAs) such as arachidonic acid (AA) required for fetal and postnatal growth. Adipose tissue is a pool of LC-PUFAs. The response of adipose tissue for the synthesis of these fatty acids in a lipid-deficient diet of dams is unknown. The aim of this study was to explore the role of maternal tissue in the synthesis of LC-PUFAs in rats fed a low-lipid diet during pregnancy and lactation. Fatty acid composition (indicative of enzymatic activity) and gene expression of encoding enzymes for fatty acid synthesis were measured in liver, mammary gland and adipose tissue in rats fed a low-lipid diet. Gene expression of desaturases, elongases, fatty acid synthase (Fasn) and their regulator Srebf-1c was increased in the mammary gland, liver and adipose tissue of rats fed a low-lipid diet compared with rats from the adequate-lipid diet group throughout pregnancy and lactation. Genes with the highest (P < 0.05) expression in the mammary gland, liver and adipose tissue were Elovl5 (1333%), Fads2 (490%) and Fasn (6608%), respectively, in a low-lipid diet than in adequate-lipid diet. The percentage of AA in the mammary gland was similar between the low-lipid diet and adequate-lipid diet groups during the second stage of pregnancy and during lactation. The percentage of monounsaturated and saturated fatty acids was significantly (P < 0.05) increased throughout pregnancy and lactation in all tissues in rats fed a low-lipid diet than in rats fed an adequate-lipid diet. Results suggest that maternal metabolic adaptations used to compensate for lipid-deficient diet during pregnancy and lactation include increased expression of genes involved in LC-PUFAs synthesis in a stage- and tissue-specific manner and elevated lipogenic activity (saturated and monounsaturated fatty acid synthesis) of maternal tissues including adipose tissue.     

Degradation of myelin basic protein by a membrane-associated metalloprotease: Neural distribution of the enzyme

A metalloprotease activity associated with myelin membrane preparations degrades myelin basic protein (MBP), generating a characteristic fragment designated peptide C (MBP 74-170). Using an immunoblotting assay, peptide C-generating activity was detected in mammalian, avian, reptilian, and amphibian brains. The activity was present in rat brain as early as postnatal day 1 and also in adult rat peripheral nerve. Immunohistochemistry with a monoclonal antibody to the purified enzyme revealed that the metalloprotease was present in oligodendrocytes of optic nerve, of both white and grey matter of spinal cord, and also in the cytoplasm of both myelinating and non-myelinating Schwann cells of peripheral nerve.Special issue dedicated to Dr. Alan N. Davison     

Increased maternal fat consumption during pregnancy alters body composition in neonatal mice

Maternal overnutrition prior to and during gestation causes pronounced metabolic dysfunction in the adult offspring. However, less is known about metabolic adaptations in the offspring that occur independently of postnatal growth and nutrition. Therefore, we evaluated the impact of excess maternal dietary lipid intake on the in utero programming of body composition, hepatic function, and hypothalamic development in newborn (P0) offspring. Female mice were fed a low-fat (LF) or high-fat (HF) diet and were mated after 4, 12, and 23 wk. A subset of the obese HF dams was switched to the LF diet during the second (DR2) or third (DR3) pregnancies. The HF offspring accrued more fat mass than the LF pups, regardless of duration of maternal HF diet consumption or prepregnancy maternal adiposity. Increased neonatal adiposity was not observed in the DR3 pups. Liver weights were reduced in the HF offspring but not in the DR2 or DR3 pups. Offspring hepatic triglyceride content was reduced in the HF pups, but hepatic inflammation and expression of lipid metabolism genes were largely unaffected by maternal diet. Maternal diet did not alter the hypothalamic expression of orexigenic and anorexigenic neuropeptides in the offspring. Thus, the intrauterine programming of increased neonatal adiposity and reduced liver size by maternal overnutrition is evident in mice at birth and occurs prior to the development of maternal obesity. These observations demonstrate that dietary intervention during pregnancy minimizes the deleterious effects of maternal obesity on offspring body composition, potentially reducing the offsprings' risk of developing obesity and related diseases later in life.     

Insulin sensitivity linked skeletal muscle Nr4a1 DNA methylation is programmed by the maternal diet and modulated by voluntary exercise in mice

Perinatal maternal high-fat consumption is known to increase the obesity and type 2 diabetes susceptibility and to impair exercise performance in the offspring. We hypothesize that epigenetic modifications in the skeletal muscle are partly responsible for this phenotype. To detect skeletal muscle genes affected by maternal nutrition, male offspring of low-fat (LF) and high-fat (HF) diet fed dams (BL6 mice) received LF diet upon weaning and were sacrificed at 6 or 25 weeks of age. Gene expression of Musculus quadriceps was investigated by microarray analysis revealing an up-regulation of the nuclear receptor Nr4a1 by maternal HF feeding. This was accompanied by promoter hypomethylation of CpG_-1408 which correlated with increased Nr4a1 gene expression at both ages. Offspring voluntary exercise training (by supplying running wheels from 7 to 25 weeks of age) normalized Nr4a1 methylation and gene expression respectively, and ameliorated the negative effects of maternal HF feeding on insulin sensitivity. Overall, Nr4a1 gene expression in skeletal muscle correlated with higher insulin levels during an oral glucose tolerance test and could, therefore, be involved in programming type 2 diabetes susceptibility in offspring exposed to perinatal high fat diet.     

Nutrition has a pervasive impact on cardiac microRNA expression in isogenic mice

The complex interaction between obesity, Western-style diets, and cardiovascular disease is of increasing interest, with a growing number of children being born to obese parents with poor lifestyle choices. These offspring have themselves an increased susceptibility to obesity and subsequent cardiovascular disease in adult life, which may be ‘programmed’ by their intrauterine environment. Cardiac microRNAs (miRNAs) are affected by multiple disease states, and have also been shown to be capable of exerting a hormone-like control on whole body metabolism. Here we sought to determine the effect of prenatal exposure to maternal obesity and/or postnatal exposure to a Western diet on miRNA expression in the heart. Unbiased small RNA sequencing was carried out on cardiac tissue from young adult mice born to lean or obese mothers; offspring were weaned onto either a low-fat control diet or a high-fat Western-style diet. We found 8 cardiac miRNAs that were significantly altered in response to maternal obesity, but only when the offspring were challenged postnatally with the Western diet. In contrast, postnatal exposure to the diet alone induced significant changes to the expression of a much larger number of miRNAs (33 in offspring of lean and 46 in offspring of obese). Many of the affected miRNAs have previously been implicated in various cardiac pathologies. The pervasive cardiac miRNA changes induced by a Western diet suggest that an individual's lifestyle choices outweigh the impact of any programming effects by maternal obesity on miRNA-related cardiac health.     

Maternal high-fat diet affects Msi/Notch/Hes signaling in neural stem cells of offspring mice

Numerous research have begun to reveal the importance of maternal nutrition in offspring brain development. Particularly, the maternal obesity or exposure to high-fat diet has been strongly suggested to exert irreversible impact on the structure and function of offspring's brain. However, it remains obscure about whether neonatal neural stem cells (NSCs) in offspring's brain are susceptible to maternal exposure to high-fat diet. Here we focused on the alternation in the Notch signaling in NSCs derived from neonatal mice, which had been given birth by female mice with a high-fat diet and found that, in fact, the high-fat diet administration imposed effects on not only maternal mice, indicated by the accumulation of viscera fat as well as the increase in body weight and serum total cholesterol, but also NSCs in the offspring’s brain, where significant increase was observed in the expression of genes, either downstream of Notch signaling or regulating this pathway, which have been shown essential for the maturation of NSCs. Therefore, our data provided the first evidence for the potential effect of maternal exposure to the high-fat diet on the Notch signaling pathway in offspring’s NSCs, indicating this altered signaling response might contribute to a profound change in offspring’s brains as a result of maternal high-fat diet prior to and during gestation.     

Maternal consumption of low-isoflavone soy protein isolate alters hepatic gene expression and liver development in rat offspring

In utero environment is known to affect fetal development. Especially, the distinct fetal programming of carcinogenesis was reported in offspring exposed to maternal diets containing soy protein isolate (SPI) or genistein. Therefore, we investigated whether maternal consumption of low-isoflavone SPI or genistein alters hepatic gene expression and liver development in rat offspring. Female Sprague–Dawley rats were fed a casein diet, a low-isoflavone SPI diet or a casein diet supplemented with genistein (250 mg/kg diet) for 2 weeks before mating and throughout pregnancy and lactation. Male offspring were studied on postnatal day 21 (CAS, SPI and GEN groups). Among 965 differentially expressed hepatic genes related to maternal diet (P<.05), the expression of 590 was significantly different between CAS and SPI groups. Conversely, the expression of 88 genes was significantly different between CAS and GEN groups. Especially, genes involved in drug metabolism were significantly affected by the maternal diet. SPI group showed increased cell proliferation, reduced apoptosis and activation of the mTOR pathway, which may contribute to a higher relative liver weight compared to other groups. We observed higher serum homocysteine levels and lower global and CpG site-specific DNA methylation of Gadd45b, a gene involved in cell proliferation and apoptosis, in SPI group compared to CAS group. Maternal SPI diet also reduced histone H3-Lysine 9 (H3K9) trimethylation and increased H3K9 acetylation in offspring. These results demonstrate that maternal consumption of a low-isoflavone SPI diet alters the hepatic gene expression profile and liver development in offspring possibly by epigenetic processes.     

Protein kinase C in rat brain myelin

It has been suggested that phosphorylation of myelin basic protein (MBP) in CNS is catalyzed by protein kinase C (PKC). In order to demonstrate that PKC in the myelin phosphorylates MBP, PKC was partially purified from rat CNS myelin by solubilization with Triton X-100 followed by a DEAE-cellulose column. MBP and histone III-S were phosphorylated in the presence of Ca²⁺ and phospholipid by rat myelin PKC. High voltage electrophoresis revealed that the phosphoamino acids in MBP by this kinase was serine residue, which is known to be the amino acid phosphorylated by PKC. The activity of PKC extracted from myelin was inhibited by the addition of psychosine to the incubation mixture. To confirm the presence of PKC molecule and to identify the isoform of PKC in the myelin, the solubilized myelin fraction was applied on SDS-PAGE, transferred to a nitrocellulose sheet and stained with anti-PKC monoclonal antibodies. Rat CNS myelin contained the PKC of about 80 kDa (intact PKC), and no proteolytic fragments were observed. PKC isozymes in myelin were type II and III. A developmental study from 14 to 42 postnatal days showed that PKC activity in CNS myelin seemed to parallel the deposition of myelin protein.