Neurobehavioral Abnormalities in Offspring of Young Adult Male Rats With a History of Traumatic Brain Injury.

Children of parents with traumatic brain injury (TBI) are more likely to develop psychiatric disorders. This association is usually attributed to TBI-induced changes in parents' personality and families' social environment. We tested the hypothesis that offspring of young adult male rats with TBI develop neurodevelopmental abnormalities in the absence of direct social contact with sires. Male Sprague-Dawley rats (F0 generation) in the TBI group underwent moderate TBI via a midline fluid percussion injury that involved craniectomy under sevoflurane (SEVO) anesthesia for 40 min on post-natal Day 60 (P60), while F0 rats in the control group were placed in a new cage, one per cage, for the equivalent time duration. A subset of F0 rats was sacrificed on P66 to assess acute changes in hypothalamic-pituitary-adrenal (HPA) axis and inflammation markers. The remaining F0 males were mated with naive females on P90 to generate offspring (F1 generation). The F0 males and F1 males and females were sequentially evaluated in the elevated plus maze, for pre-pulse inhibition of acoustic startle, in the Morris water maze, and for resting and stress levels of serum corticosterone starting on ∼P105 (F0) and ∼P60 (F1), followed by tissue collection for further analyses. Acutely, the F0 TBI males had messenger RNA (mRNA) transcripts altered to support an increased hypothalamic and hippocampal Na+-K+-Cl- (Slc12a2) Cl- importer / K+-2Cl- (Slc12a5) Cl- exporter ratio and decreased hippocampal glucocorticoid receptors (Nr3c1), as well as increased serum levels of corticosterone, interleukin-1ß (IL-1ß), and biomarkers of activated hippocampal microglia and astrocytes. Long-term, F0 TBI rats exhibited increased corticosterone concentrations at rest and under stress, anxiety-like behavior, impaired sensory-motor gating, and impaired spatial memory. These abnormalities were underpinned by reduced mRNA levels of hypothalamic and hippocampal mineralocorticoid receptors (Nr3c2), hippocampal Nr3c1, and hypothalamic brain-derived neurotrophic factor (Bdnf), as well as elevated serum levels of IL-1ß, and biomarkers of activated hippocampal microglia and astrocytes. F1 male offspring of TBI sires exhibited abnormalities in all behavioral tests, while their F1 female counterparts had abnormal pre-pulse inhibition responses only. F1 male offspring of TBI sires also had reduced mRNA levels of hippocampal Nr3c1 and Nr3c2, as well as hypothalamic and hippocampal Bdnf, whereas increases in inflammatory markers were more profound in F1 females. These findings suggest that offspring of sires with a history of a moderate TBI that involved craniectomy under SEVO anesthesia for 40 min, develop sex-dependent neurobehavioral abnormalities in the absence of direct social interaction between the sire and the offspring.

Intergenerational Perioperative Neurocognitive Disorder.

Accelerated neurocognitive decline after general anesthesia/surgery, also known as perioperative neurocognitive disorder (PND), is a widely recognized public health problem that may affect millions of patients each year. Advanced age, with its increasing prevalence of heightened stress, inflammation, and neurodegenerative alterations, is a consistent contributing factor to the development of PND. Although a strong homeostatic reserve in young adults makes them more resilient to PND, animal data suggest that young adults with pathophysiological conditions characterized by excessive stress and inflammation may be vulnerable to PND, and this altered phenotype may be passed to future offspring (intergenerational PND). The purpose of this narrative review of data in the literature and the authors' own experimental findings in rodents is to draw attention to the possibility of intergenerational PND, a new phenomenon which, if confirmed in humans, may unravel a big new population that may be affected by parental PND. In particular, we discuss the roles of stress, inflammation, and epigenetic alterations in the development of PND. We also discuss experimental findings that demonstrate the effects of surgery, traumatic brain injury, and the general anesthetic sevoflurane that interact to induce persistent dysregulation of the stress response system, inflammation markers, and behavior in young adult male rats and in their future offspring who have neither trauma nor anesthetic exposure (i.e., an animal model of intergenerational PND).

LncRNA CASC11 upregulation promotes HDAC4 to alleviate oxidized low-density lipoprotein-induced injury of cardiac microvascular endothelial cells.

Long noncoding RNAs (LncRNAs) are essential to regulate the pathogenesis of coronary artery disease (CAD). This study was conducted to analyze the functionality of long noncoding RNA cancer susceptibility candidate 11 (lncRNA CASC11) in oxidized low-density lipoprotein (ox-LDL)-induced injury of cardiac microvascular endothelial cells (CMECs). CMECs were treated with ox-LDL to induce the CAD cell model. The cellular expression levels of CASC11 and histone deacetylase 4 (HDAC4) were determined by real-time quantitative polymerase chain reaction or Western blot assay. Cell absorbance, apoptosis, angiogenesis, and inflammation were evaluated by cell counting kit-8, flow cytometry, tube formation, and enzyme-linked immunosorbent assays. The subcellular localization of CASC11 was examined by the nuclear/cytoplasmic fractionation assay. The binding of human antigen R (HuR) to CASC11 and HDAC4 was analyzed by RNA immunoprecipitation. HDAC4 stability was determined after actinomycin D treatment. CASC11 was found to be decreased in the CAD cell model. CASC11 upregulation increased cell viability and angiogenesis and reduced apoptosis and inflammation. CASC11 bound to HuR and improved HDAC4 expression. HDAC4 downregulation counteracted the protective role of CASC11 overexpression in CMECs. In summary, CASC11 alleviated ox-LDL-induced injury of CMECs by binding to HuR and stabilizing HDAC4.

A Preliminary Study of Immediate Intraperitoneal Chemotherapy for Stage III Colorectal Cancer.

OBJECTIVES: Investigate the survival of patients with stage III colorectal cancer (CRC) treated with immediate postoperative intraperitoneal chemotherapy. METHODS: The clinical data of 195 patients with stage III CRC admitted to The First Affiliated Hospital of Wenzhou Medical University from June 2017 to June 2018 were retrospectively analyzed. The patients were divided into an observation group and a control group, both groups were treated with the routine laparoscopic radical operation, on the basis of which, the patients in the observation group were treated with intraperitoneal perfusion chemotherapy during the operation. The local recurrence, abdominal cavity metastasis, and liver metastasis were followed up, and the time of disease recurrence and total survival were recorded. RESULTS: The survival analysis showed that there was a significant difference in progression-free survival (χ 2 = 5.416, P = 0.020) and overall survival (χ 2 = 4.673, P = 0.031) between the observation group and the control group. CONCLUSIONS: During laparoscopic radical resection of CRC, the use of intraperitoneal chemotherapy with raltitrexed can achieve satisfactory results and improve the survival rate of patients with stage III CRC, perioperative use of raltitrexed has been shown to be beneficial in terms of overall survival and progression-free survival.

Melanin-like polydopamine nanoparticles mediating anti-inflammatory and rescuing synaptic loss for inflammatory depression therapy.

Inflammatory depression is closely related to neuroinflammation. However, current anti-inflammatory drugs have low permeability to cross blood-brain barrier with difficulties reaching the central nervous system to provide therapeutic effectiveness. To overcome this limitation, the nano-based drug delivery technology was used to synthesize melanin-like polydopamine nanoparticles (PDA NPs) (~ 250 nm) which can cross the blood-brain barrier. Importantly, PDA NPs with abundant phenolic hydroxyl groups function as excellent free radical scavengers to attenuate cell damage caused by reactive oxygen species or acute inflammation. In vitro experiments revealed that PDA NPs exhibited excellent antioxidative properties. Next, we aimed to investigate the therapeutic effect of PDA NPs on inflammatory depression through intraperitoneal injection to the lipopolysaccharide-induced inflammatory depression model in mice. PDA NPs significantly reversed the depression-like behavior. PDA NPs was also found to reduce the peripheral and central inflammation induced by LPS, showing that alleviated splenomegaly, reduced serum inflammatory cytokines, inhibited microglial activation and restored synaptic loss. Various experiments also showed that PDA NPs had good biocompatibility both in vivo and in vitro. Our work suggested that PDA NPs may be biocompatible nano-drugs in treating inflammatory depression but their clinical application requires further study.

Intergenerational Perioperative Neurocognitive Disorder in Young Adult Male Rats with Traumatic Brain Injury.

BACKGROUND: The authors tested the hypothesis that the effects of traumatic brain injury, surgery, and sevoflurane interact to induce neurobehavioral abnormalities in adult male rats and in their offspring (an animal model of intergenerational perioperative neurocognitive disorder). METHODS: Sprague-Dawley male rats (assigned generation F0) underwent a traumatic brain injury on postnatal day 60 that involved craniectomy (surgery) under 3% sevoflurane for 40 min followed by 2.1% sevoflurane for 3 h on postnatal days 62, 64, and 66 (injury group). The surgery group had craniectomy without traumatic brain injury, whereas the sevoflurane group had sevoflurane only. On postnatal day 90, F0 males and control females were mated to generate offspring (assigned generation F1). RESULTS: Acutely, F0 injury rats exhibited the greatest increases in serum corticosterone and interleukin-1ß and -6, and activation of the hippocampal microglia. Long-term, compared to controls, F0 injury rats had the most exacerbated corticosterone levels at rest (mean ± SD, 2.21 ± 0.64 vs. 7.28 ± 1.95 ng/ml, n = 7 - 8; P < 0.001) and 10 min after restraint (133.12 ± 33.98 vs. 232.83 ± 40.71 ng/ml, n = 7 - 8; P < 0.001), increased interleukin-1ß and -6, and reduced expression of hippocampal glucocorticoid receptor (Nr3c1; 0.53 ± 0.08 fold change relative to control, P < 0.001, n = 6) and brain-derived neurotrophic factor genes. They also exhibited greater behavioral deficiencies. Similar abnormalities were evident in their male offspring, whereas F1 females were not affected. The reduced Nr3c1 expression in F1 male, but not female, hippocampus was accompanied by corresponding Nr3c1 promoter hypermethylated CpG sites in F0 spermatozoa and F1 male, but not female, hippocampus. CONCLUSIONS: These findings in rats suggest that young adult males with traumatic brain injury are at an increased risk of developing perioperative neurocognitive disorder, as are their unexposed male but not female offspring.

Dexmedetomidine Diminishes, but Does Not Prevent, Developmental Effects of Sevoflurane in Neonatal Rats.

BACKGROUND: Sevoflurane (SEVO) increases neuronal excitation in neonatal rodent brains through alteration of gamma aminobutyric acid (GABA)(A) receptor signaling and increases corticosterone release. These actions may contribute to mechanisms that initiate the anesthetic's long-term neuroendocrine and neurobehavioral effects. Dexmedetomidine (DEX), a non-GABAergic α2-adrenergic receptor agonist, is likely to counteract SEVO-induced neuronal excitation. We investigated how DEX pretreatment may alter the neurodevelopmental effects induced by SEVO in neonatal rats. METHODS: Postnatal day (P) 5 Sprague-Dawley male rats received DEX (25 µg/kg, intraperitoneal) or vehicle before exposure to 2.1% SEVO for 6 hours (the DEX + SEVO and SEVO groups, respectively). Rats in the DEX-only group received DEX without exposure to SEVO. A subcohort of P5 rats was used for electroencephalographic and serum corticosterone measurements. The remaining rats were sequentially evaluated in the elevated plus maze on P80, prepulse inhibition of the acoustic startle response on P90, Morris water maze (MWM) starting on P100, and for corticosterone responses to physical restraint for 30 minutes on P120, followed by assessment of epigenomic DNA methylation patterns in the hippocampus. RESULTS: Acutely, DEX depressed SEVO-induced electroencephalogram-detectable seizure-like activity (mean ± SEM, SEVO versus DEX + SEVO, 33.1 ± 5.3 vs 3.9 ± 5.3 seconds, P < .001), but it exacerbated corticosterone release (SEVO versus DEX + SEVO, 169.935 ± 20.995 versus 280.853 ± 40.963 ng/mL, P = .043). DEX diminished, but did not fully abolish, SEVO-induced corticosterone responses to restraint (control: 11625.230 ± 877.513, SEVO: 19363.555 ± 751.325, DEX + SEVO: 15012.216 ± 901.706, DEX-only: 12497.051 ± 999.816; F[3,31] = 16.878, P < .001) and behavioral deficiencies (time spent in the target quadrant of the MWM: control: 31.283% ± 1.722%, SEVO: 21.888% ± 2.187%, DEX + SEVO: 28.617% ± 1.501%, DEX-only: 31.339% ± 3.087%; F[3,67] = 3.944, P = .012) in adulthood. Of the 391 differentially methylated genes in the SEVO group, 303 genes in the DEX + SEVO group had DNA methylation patterns that were not different from those in the control group (ie, they were normal). DEX alone did not cause acute or long-term functional abnormalities. CONCLUSIONS: This study suggests that the ability of DEX to depress SEVO-induced neuronal excitation, despite increasing corticosterone release, is sufficient to weaken mechanisms leading to long-term neuroendocrine/neurobehavioral abnormalities. DEX may prevent changes in DNA methylation in the majority of genes affected by SEVO, epigenetic modifications that could predict abnormalities in a wide range of functions.

The potential role of stress and sex steroids in heritable effects of sevoflurane†.

Most surgical procedures require general anesthesia, which is a reversible deep sedation state lacking all perception. The induction of this state is possible because of complex molecular and neuronal network actions of general anesthetics (GAs) and other pharmacological agents. Laboratory and clinical studies indicate that the effects of GAs may not be completely reversible upon anesthesia withdrawal. The long-term neurocognitive effects of GAs, especially when administered at the extremes of ages, are an increasingly recognized health concern and the subject of extensive laboratory and clinical research. Initial studies in rodents suggest that the adverse effects of GAs, whose actions involve enhancement of GABA type A receptor activity (GABAergic GAs), can also extend to future unexposed offspring. Importantly, experimental findings show that GABAergic GAs may induce heritable effects when administered from the early postnatal period to at least young adulthood, covering nearly all age groups that may have children after exposure to anesthesia. More studies are needed to understand when and how the clinical use of GAs in a large and growing population of patients can result in lower resilience to diseases in the even larger population of their unexposed offspring. This minireview is focused on the authors' published results and data in the literature supporting the notion that GABAergic GAs, in particular sevoflurane, may upregulate systemic levels of stress and sex steroids and alter expressions of genes that are essential for the functioning of these steroid systems. The authors hypothesize that stress and sex steroids are involved in the mediation of sex-specific heritable effects of sevoflurane.

Roles of Testosterone and Estradiol in Mediation of Acute Neuroendocrine and Electroencephalographic Effects of Sevoflurane During the Sensitive Period in Rats.

Testosterone (T), predominantly acting through its derivative 17ß-estradiol (E2), regulates the brain's sexual differentiation in rodents during the perinatal sensitive period, which mirrors the window of vulnerability to the adverse effects of general anesthetics. The mechanisms of anesthesia's adverse effects are poorly understood. We investigated whether sevoflurane alters T and E2 levels and whether they contribute to sevoflurane's acute adverse effects in postnatal day 5 Sprague-Dawley rats. The rats underwent electroencephalography recordings for 2 h of baseline activity or for 1 h before and another hour during 2.1% sevoflurane exposure, followed by collection of trunk blood and brain tissue. Pharmacological agents, including the GABA type A receptor inhibitor bicuculline and the aromatase inhibitor formestane, were administered 30 min before sevoflurane anesthesia. Sevoflurane increased serum T levels in males only. All other effects of sevoflurane were similar in both sexes, including increases in serum levels of E2, hypothalamic mRNA levels of aromatase, estrogen receptor α (Erα) [not estrogen receptor ß (Erß)], Na+-K+-Cl- cotransporter (Nkcc1)/K+-Cl- cotransporter (Kcc2) mRNA ratio, electroencephalography-detectable seizures, and stress-like corticosterone secretion. Bicuculline and formestane alleviated these effects, except the T level increases. The ERα antagonist MPP, but not the ERß antagonist PHTPP, reduced electroencephalography-detectable seizures and normalized the Nkcc1/Kcc2 mRNA ratio. Collectively, sevoflurane exacerbates levels of T in males and E2 in both sexes during the period of their organizational effects in rodents. Sevoflurane acts through GABAAR-mediated, systemic T-independent elevation of E2 to cause electroencephalography-detectable seizures, stress-like corticosterone secretion, and changes in the expression of genes critical for brain development.

A Methyltransferase Inhibitor (Decitabine) Alleviates Intergenerational Effects of Paternal Neonatal Exposure to Anesthesia With Sevoflurane.

BACKGROUND: Neonatal exposure to sevoflurane induces neurobehavioral and neuroendocrine abnormalities in exposed male rats (generation F0) and neurobehavioral, but not neuroendocrine, abnormalities in their male, but not female, offspring (generation F1). These effects of sevoflurane are accompanied by a hypermethylated neuron-specific K-2Cl (Kcc2) Cl exporter gene in the F0 spermatozoa and the F1 male hypothalamus, while the gene's expression is reduced in the F0 and F1 hypothalamus. We investigated whether inhibition of deoxyribonucleic acid methyltransferases (DNMTs) before paternal sevoflurane exposure could alleviate the anesthetic's F0 and F1 effects. METHODS: Sprague-Dawley male rats were anesthetized with 2.1% sevoflurane for 5 hours on postnatal day (P) 5 and mated with control females on P90 to generate offspring. The nonselective DNMT inhibitor decitabine (0.5 mg/kg, intraperitoneally) was administered 30 minutes before sevoflurane exposure. The F0 and F1 male rats were evaluated in in vivo and in vitro tests in adulthood. RESULTS: Paternal exposure to sevoflurane induced impaired prepulse inhibition of the acoustic startle response and exacerbated corticosterone responses to stress in F0 males and impaired prepulse inhibition of the startle responses in F1 males. These effects were accompanied in both generations by reduced and increased expressions of hypothalamic Kcc2 and Dnmt3a/b, respectively. Decitabine deterred the effects of paternal exposure to sevoflurane in F0 and F1 males. CONCLUSIONS: These results suggest that similar decitabine-sensitive mechanisms regulating expression of multiple genes are involved in the mediation of neurobehavioral abnormalities in sires neonatally exposed to sevoflurane and in their future unexposed male offspring.

Neonatal exposure to sevoflurane expands the window of vulnerability to adverse effects of subsequent exposure to sevoflurane and alters hippocampal morphology via decitabine-sensitive mechanisms.

BACKGROUND: Deficiencies in neurocognitive function have been found in late childhood or adolescence in patients who had prolonged and/or repeated early-life general anesthesia. Animal studies suggest that anesthetic-induced impairment in the neuron-specific K+-2Cl- (Kcc2) Cl- exporter expression, which regulates developmental maturation of GABA type A receptor (GABAAR) signaling from excitatory to inhibitory, may play a mediating role. We tested whether the DNA methyltransferase (DNMT) inhibitor decitabine ameliorates the anesthetic's adverse effects. METHODS: Sprague-Dawley male rats were injected with vehicle or decitabine 30 min before 2.1 % sevoflurane exposure for 5 h on postnatal day 5 (P5). On P19, P20, or P21, electroencephalography-detectable seizures were measured during 1 h of sevoflurane exposure, followed by collection of the trunk blood and brain tissue samples. Other rats were evaluated for changes in hippocampal CA1 dendrite morphology and gene expressions on ≥ P120. RESULTS: Rats in the vehicle plus sevoflurane group responded to sevoflurane exposure on P19, P20 or P21 with electroencephalography-detectable seizures and stress-like corticosterone secretion and had altered hippocampal dendrite morphology in adulthood. These rats had expressions of Kcc2 and Dnmt genes downregulated and upregulated, respectively, in the P19 - P21 cortex and hypothalamus and the ≥ P120 hippocampus. All measured parameters in the sevoflurane-exposed rats that were pretreated with decitabine were not different from those in the control group. CONCLUSIONS: Neonatal exposure to sevoflurane sensitizes rats to adverse effects of repeated exposure to the anesthetic. The anesthetic-caused changes in the decitabine-sensitive mechanisms may play a mediating role in the developmental effects of early-life anesthesia.

Neuroendocrine, epigenetic, and intergenerational effects of general anesthetics.

The progress of modern medicine would be impossible without the use of general anesthetics (GAs). Despite advancements in refining anesthesia approaches, the effects of GAs are not fully reversible upon GA withdrawal. Neurocognitive deficiencies attributed to GA exposure may persist in neonates or endure for weeks to years in the elderly. Human studies on the mechanisms of the long-term adverse effects of GAs are needed to improve the safety of general anesthesia but they are hampered not only by ethical limitations specific to human research, but also by a lack of specific biological markers that can be used in human studies to safely and objectively study such effects. The latter can primarily be attributed to an insufficient understanding of the full range of the biological effects induced by GAs and the molecular mechanisms mediating such effects even in rodents, which are far more extensively studied than any other species. Our most recent experimental findings in rodents suggest that GAs may adversely affect many more people than is currently anticipated. Specifically, we have shown that anesthesia with the commonly used GA sevoflurane induces in exposed animals not only neuroendocrine abnormalities (somatic effects), but also epigenetic reprogramming of germ cells (germ cell effects). The latter may pass the neurobehavioral effects of parental sevoflurane exposure to the offspring, who may be affected even at levels of anesthesia that are not harmful to the exposed parents. The large number of patients who require general anesthesia, the even larger number of their future unexposed offspring whose health may be affected, and a growing number of neurodevelopmental disorders of unknown etiology underscore the translational importance of investigating the intergenerational effects of GAs. In this mini review, we discuss emerging experimental findings on neuroendocrine, epigenetic, and intergenerational effects of GAs.

Relationship between vascular endothelial growth factor -2578C > a gene polymorphism and lung cancer risk: a meta-analysis.

BACKGROUND: Several reports were published on the relationship between the vascular endothelial growth factor (VEGF) -2578C > A gene polymorphism and lung cancer risk; however, the results are debatable. This meta-analysis was conducted to assess the relationship between VEGF -2578C > A gene polymorphism and lung cancer risk. METHODS: The associated literatures were identified on the 1st of September 2018 from CBM-disc (China Biological Medicine Database) and PubMed. RESULT: A total of 14 reports were recruited into our meta-analysis to assess the association between VEGF -2578C > A gene polymorphism and lung cancer susceptibility. There was a marked association between VEGF -2578C > A A allele / CC genotype and lung cancer risk in overall and Asian populations (overall populations: A allele: OR = 1.26, 95% CI: 1.08-1.46, P = 0.003; CC genotype: OR = 0.72, 95% CI: 0.54-0.95, P = 0.02; Asians: A allele: OR = 1.33, 95% CI: 1.15-1.55, P = 0.0002; CC genotype: OR = 0.68, 95% CI: 0.50-0.93, P = 0.01). However, VEGF -2578C > A gene polymorphism was not associated with the risk of lung cancer in Caucasians. CONCLUSION: VEGF -2578C > A A allele / CC genotype is associated with the lung cancer susceptibility in Asians and in overall populations.

Intergenerational Effects of Sevoflurane in Young Adult Rats.

BACKGROUND: Sevoflurane administered to neonatal rats induces neurobehavioral abnormalities and epigenetic reprogramming of their germ cells; the latter can pass adverse effects of sevoflurane to future offspring. As germ cells are susceptible to reprogramming by environmental factors across the lifespan, the authors hypothesized that sevoflurane administered to adult rats could induce neurobehavioral abnormalities in future offspring, but not in the exposed rats themselves. METHODS: Sprague-Dawley rats were anesthetized with 2.1% sevoflurane for 3 h every other day between postnatal days 56 and 60. Twenty-five days later, exposed rats and nonexposed controls were mated to produce offspring. RESULTS: Adult male but not female offspring of exposed parents of either sex exhibited deficiencies in elevated plus maze (mean ± SD, offspring of both exposed parents vs. offspring of control parents, 35 ± 12 vs. 15 ± 15 s, P < 0.001) and prepulse inhibition of acoustic startle (offspring of both exposed parents vs. offspring of control parents, 46.504 ± 13.448 vs. 25.838 ± 22.866%, P = 0.009), and increased methylation and reduced expression of the potassium ion-chloride ion cotransporter KCC2 gene (Kcc2) in the hypothalamus. Kcc2 was also hypermethylated in sperm and ovary of the exposed rats. Surprisingly, exposed male rats also exhibited long-term abnormalities in functioning of the hypothalamic-pituitary-gonadal and -adrenal axes, reduced expression of hypothalamic and hippocampal Kcc2, and deficiencies in elevated plus maze (sevoflurane vs. control, 40 ± 24 vs. 25 ± 12 s, P = 0.038) and prepulse inhibition of startle (sevoflurane vs. control, 39.905 ± 21.507 vs. 29.193 ± 24.263%, P < 0.050). CONCLUSIONS: Adult sevoflurane exposure affects brain development in male offspring by epigenetically reprogramming both parental germ cells, while it induces neuroendocrine and behavioral abnormalities only in exposed males. Sex steroids may be required for mediation of the adverse effects of adult sevoflurane in exposed males.

The role of ERCC1 and AFP gene polymorphism in hepatocellular carcinoma.

The aim of this study was to evaluate the effects of polymorphisms in excision repair cross-complementation group 1 (ERCC1) and alpha-fetoprotein (AFP) genes and their haplotypes on the susceptibility to hepatocellular carcinoma (HCC), and to decipher the association between single-nucleotide polymorphisms (SNPs) and clinicopathologic characteristics of HCC.Peripheral blood DNA was extracted from 206 subjects. SNaPshot technique was used for genotyping 5 SNP sites of the ERCC1 rs735482, rs1046282, rs3212948, and AFP rs737241, rs4024 genotypes. Chi-squared test and logistic regression model were used to analyze the relationship of different genotypes or haplotype and the susceptibility and clinicopathologic characteristics of HCC.The frequency of GG.GA and AA genotypes at the AFP rs737241 site in the case and control groups showed statistically significant differences (P < .05). The risk of HCC in subjects carrying mutated allele A (GA+AA) was increased by 0.543-times (P < .05) compared to that in the subjects with the GG genotype. Significant differences were observed in the linkage disequilibrium between 2 of the five SNPs (P < .05); the frequency of ERCC1 C-C and AFP A-A haplotypes was significantly lower in the case group than in the control group (P < .05). The results of clinicopathologic analysis showed that A allele at the rs737241 locus could increase the expression level of AFP (P = .007), the rs1046282 mutation C allele could increase the AFP expression level (P = .011), rs4024 locus mutation A allele could reduce the risk of vascular invasion (P = .013), rs3212948 locus mutation T allele could reduce the differentiation of liver cancer (P = .022), rs1046282 locus C allele could reduce the DNA load of hepatitis B virus (P = .035), and rs735482 A allele could increase the tumor size in HCC (P = .037).The SNPs in rs737241 for AFP gene may correlate with the occurrence of HCC. The SNPs in ERCC1 and AFP genes may affect the prognosis of HCC, offering reliable information for early prediction of tumor progression and diagnosis of HCC.

Dendrobium polysaccharides attenuate cognitive impairment in senescence-accelerated mouse prone 8 mice via modulation of microglial activation.

Dendrobium is one of the most important traditional Chinese medicinal foods used to treat age-related disorders. However, it remains unclear whether Dendrobium affects the progression of Alzheimer's disease (AD). In the present study, we investigated the effects of Dendrobium officinale polysaccharides (DOP) on the BV2 microglial cell line and the senescence-accelerated mouse prone 8 (SAMP8) mouse strain. In vitro experiments showed that DOP pretreatment contributed to BV2 cells shifting from proinflammatory to anti-inflammatory phenotypes with enhanced Aß clearance in response to Aß insults. For the in vivo study, mice were chronically treated with DOP in drinking water from 4 to 7 months of age. The results showed that DOP remarkably attenuated cognitive decline in SAMP8 mice. DOP also inhibited the increased hippocampal microglial activation in SAMP8 mice with downregulation of interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), while interleukin-10 (IL-10), neprilysin (NEP) and insulin-degrading enzyme (IDE) were upregulated. The accumulation of hippocampal Aß42 and phosphated Tau proteins in SAMP8 mice was also reduced. Taken together, our data suggest that Dendrobium has the potential to provide neuroprotection against AD-related cognitive impairment via modulation of microglial activation.

Assessment of Seven Clinical Tumor Markers in Diagnosis of Non-Small-Cell Lung Cancer.

BACKGROUND: The correlation between tumor markers (TM) and TNM stage of non-small-cell lung cancer (NSCLC) has not been widely reported. METHODS: TM levels (CEA, CA125, CA15-3, CA19-9, CA72-4, CYFRA21-1, and SCC-Ag) in 424 cases of lung adenocarcinoma (LAC), 166 cases of lung squamous cell carcinoma (LSCC), and 103 cases of benign chest disease (BCD) were analyzed before treatment. RESULTS: By Kendall's tau-b correlation analysis, CEA, CA125, CA15-3, CA19-9, CA72-4, CYFRA21-1, and SCC-Ag were correlated with T stage of LAC (r = 0.235, p < 0.05; r = 0.298, p < 0.05; r = 0.254, p < 0.05; r = 0.063, p < 0.05; r = 0.080, p < 0.05; r = 0.268, p < 0.05; and r = 0.080, p < 0.05). CEA, CA125, CA15-3, CA19-9, CA72-4, and CYFRA21-1 were correlated with N stage of LAC (r = 0.356, p < 0.05; r = 0.415, p < 0.05; r = 0.340, p < 0.05; r = 0.117, p < 0.05; r = 0.175, p < 0.05; and r = 0.351, p < 0.05). CEA, CA125, CA15-3, CA19-9, CA72-4, and CYFRA21-1 were correlated with M stage of LAC (r = 0.365, p < 0.05; r = 0.353, p < 0.05; r = 0.293, p < 0.05; r = 0.135, p < 0.05; r = 0.169, p < 0.05; and r = 0.312, p < 0.05). CA125, CYFRA21-1, and SCC-Ag were correlated with T stage of LSCC (r = 0.202, p < 0.05; r = 0.233, p < 0.05; and r = 0.099, p < 0.05). CA125 and CYFRA21-1 were correlated with N stage of LSCC (r = 0.178, p < 0.05 and r = 0.284, p < 0.05). CA125, CA15-3, and CYFRA21-1 were correlated with M stage of LSCC (r = 0.214, p < 0.05; r = 0.152, p < 0.05; and r = 0.213, p < 0.05). Combining hazard ratio, AUC, sensitivity, specificity, NPV, and PPV, it was concluded that CEA and CYFRA21-1were the most related TM of LAC. SCC-Ag and CYFRA21-1 were the most related TM of LSCC. CONCLUSIONS: CEA combined with CYFRA21-1 contributed to auxiliary diagnosis of LAC. CYFRA21-1 combined with SCC-Ag contributed to auxiliary diagnosis of LSCC. CEA, CA125, CA15-3, CA19-9, CA72-4, and CYFRA21-1 were correlated with primary tissue and metastasis of LAC. CA125 and CYFRA21-1 were correlated with primary tissue and metastasis of LSCC.

The Combination of Long-term Ketamine and Extinction Training Contributes to Fear Erasure by Bdnf Methylation.

A combination of antidepressant drugs and psychotherapy exhibits more promising efficacy in treating fear disorders than either treatment alone, but underlying mechanisms of such treatments remain largely unknown. Here we investigated the role of DNA methylation of the brain-derived neurotrophic factor (Bdnf) gene in the therapeutic effects of ketamine in combination with extinction training in a mouse model of post-traumatic stress disorder (PTSD) induced by inescapable electric foot shocks (IFS). Male mice received ketamine for 22 consecutive days starting 1 h after the IFS (long-term ketamine treatment) or 2 h prior to the extinction training on days 15 and 16 after the IFS (short-term ketamine treatment). The Open Field (OF) and Elevated Plus Maze (EPM) tests were conducted on days 18 and 20. The spontaneous recovery and fear renewal tests were performed on day 23. Mice, subjected to IFS, exhibited anxiety-like behavior and fear relapse, accompanied by the increased levels of DNA methyltransferases, hyper-methylation of Bdnf gene, and decreased BDNF mRNA expression in the medial prefrontal cortex (mPFC) and hippocampus (HIP). Long-term treatment with ketamine combined with extinction training alleviated the IFS-induced abnormalities. These results suggest that long-term ketamine treatment in combination with extinction training may ameliorate fear relapse in the murine model of PTSD, at least in part, by normalizing DNA methylation of Bdnf gene.

Role of environmental stressors in determining the developmental outcome of neonatal anesthesia.

BACKGROUND: The majority of studies evaluating neurocognition in humans who had procedures under anesthesia early in life found long-term deficits even though the typical anesthesia duration normalized to the human life span is much shorter than that shown to induce developmental abnormalities in rodents. Therefore, we studied whether subsequent environmental stressors contribute to deficiencies programmed by a brief neonatal etomidate exposure. METHODS: Postnatal days (P) 4, 5, or 6, Sprague-Dawley rats, pretreated with vehicle or the Na+-K+-2Cl- (NKCC1) inhibitor, bumetanide, received two injections of etomidate resulting in anesthesia for 2h. To simulate stress after anesthesia, the animals were exposed to a single maternal separation for 3h at P10. 3-7days after exposure to etomidate the rats had increased hypothalamic NKCC1 mRNA and corticotropin releasing hormone (CRH) mRNA and decreased K+-2Cl- (KCC2) mRNA levels with greater changes in males. In rats neonatally exposed to both etomidate and maternal separation, these abnormalities persisted into adulthood. These animals also exhibited extended corticosterone responses to restraint stress with increases in total plasma corticosterone more robust in males, as well as behavioral abnormalities. Pretreatment with the NKCC1 inhibitor ameliorated most of these effects. CONCLUSIONS: Post-anesthesia stressors may exacerbate/unmask neurodevelopmental abnormalities even after a relatively short anesthetic with etomidate, leading to dysregulated stress response systems and neurobehavioral deficiencies in adulthood. Amelioration by bumetanide suggests a mechanistic role for etomidate-enhanced gamma-aminobutyric acid type A receptor-mediated depolarization in initiating long-lasting alterations in gene expression that are further potentiated by subsequent maternal separation.