Reduction characteristic of chlorobenzene by a newly isolated Paenarthrobacter ureafaciens LY from a pharmaceutical wastewater treatment plant.

A highly efficient chlorobenzene-degrading strain was isolated from the sludge of a sewage treatment plant associated with a pharmaceutical company. The strain exhibited a similarity of over 99.9% with multiple strains of Paenarthrobacter ureafaciens. Therefore, the strain was suggested to be P. ureafaciens LY. This novel strain exhibited a broad spectrum of pollutant degradation capabilities, effectively degrading chlorobenzene and other organic pollutants, such as 1, 2, 4-trichlorobenzene, phenol, and xylene. Moreover, P. ureafaciens LY co-metabolized mixtures of chlorobenzene with 1, 2, 4-trichlorobenzene or phenol. Evaluation of its degradation efficiency showed that it achieved an impressive degradation rate of 94.78% for chlorobenzene within 8 h. The Haldane-Andrews model was used to describe the growth of P. ureafaciens LY under specific pollutants and its concentrations, revealing a maximum specific growth rate (µmax ) of 0.33 h-1 . The isolation and characterization of P. ureafaciens LY, along with its ability to degrade chlorobenzene, provides valuable insights for the development of efficient and eco-friendly approaches to mitigate chlorobenzene contamination. Additionally, investigation of the degradation performance of the strain in the presence of other pollutants offers important information for understanding the complexities of co-metabolism in mixed-pollutant environments.

JMJD6 protects against isoproterenol-induced cardiac hypertrophy via inhibition of NF-κB activation by demethylating R149 of the p65 subunit.

Histone modification plays an important role in pathological cardiac hypertrophy and heart failure. In this study we investigated the role of a histone arginine demethylase, Jumonji C domain-containing protein 6 (JMJD6) in pathological cardiac hypertrophy. Cardiac hypertrophy was induced in rats by subcutaneous injection of isoproterenol (ISO, 1.2 mg·kg-1·d-1) for a week. At the end of the experiment, the rats underwent echocardiography, followed by euthanasia and heart collection. We found that JMJD6 levels were compensatorily increased in ISO-induced hypertrophic cardiac tissues, but reduced in patients with heart failure with reduced ejection fraction (HFrEF). Furthermore, we demonstrated that JMJD6 overexpression significantly attenuated ISO-induced hypertrophy in neonatal rat cardiomyocytes (NRCMs) evidenced by the decreased cardiomyocyte surface area and hypertrophic genes expression. Cardiac-specific JMJD6 overexpression in rats protected the hearts against ISO-induced cardiac hypertrophy and fibrosis, and rescued cardiac function. Conversely, depletion of JMJD6 by single-guide RNA (sgRNA) exacerbated ISO-induced hypertrophic responses in NRCMs. We revealed that JMJD6 interacted with NF-κB p65 in cytoplasm and reduced nuclear levels of p65 under hypertrophic stimulation in vivo and in vitro. Mechanistically, JMJD6 bound to p65 and demethylated p65 at the R149 residue to inhibit the nuclear translocation of p65, thus inactivating NF-κB signaling and protecting against pathological cardiac hypertrophy. In addition, we found that JMJD6 demethylated histone H3R8, which might be a new histone substrate of JMJD6. These results suggest that JMJD6 may be a potential target for therapeutic interventions in cardiac hypertrophy and heart failure.

Roles and mechanisms of phospholipid transfer protein in the development of Alzheimer's disease.

Phospholipid transfer protein (PLTP) is a complex glycosylated protein that mediates the transfer of phospholipids, unesterified cholesterol, diacylglycerides, specific apolipoproteins, and tocopherols between different classes of lipoproteins as well as between lipoproteins and cells. Many studies have associated PLTP with a variety of lipid metabolic diseases. However, recent studies have indicated that PLTP is highly expressed in the brain of vertebrate and may be related to many central nervous system diseases, such as Alzheimer's disease. Here, we review the data and report the role and mechanisms PLTP in Alzheimer's disease.

The Phosphodiesterase-4 Inhibitor Roflumilast, a Potential Treatment for the Comorbidity of Memory Loss and Depression in Alzheimer's Disease: A Preclinical Study in APP/PS1 Transgenic Mice.

BACKGROUND: Depression is highly related to Alzheimer's disease (AD), yet no effective treatment is available. Phosphodiesterase-4 (PDE4) has been considered a promising target for treatment of AD and depression. Roflumilast, the first PDE4 inhibitor approved for clinical use, improves cognition at doses that do not cause side effects such as emesis. METHODS: Here we examined the effects of roflumilast on behavioral dysfunction and the related mechanisms in APPswe/PS1dE9 transgenic mice, a widely used model of AD. Mice at 10 months of age were examined for memory in the novel object recognition and Morris water-maze tests and depression-like behavior in the tail-suspension test and forced swimming test before killing for neurochemical assays. RESULTS: In the novel object recognition and Morris water-maze, APPswe/PS1dE9 mice showed significant cognitive declines, which were reversed by roflumilast at 5 and 10 mg/kg orally once per day. In the tail-suspension test and forced swimming test, the AD mice showed prolonged immobility time, which was also reversed by roflumilast. In addition, the staining of hematoxylin-eosin and Nissl showed that roflumilast relieved the neuronal cell injuries, while terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling analysis indicated that roflumilast ameliorated cell apoptosis in AD mice. Further, roflumilast reversed the decreased ratio of B-cell lymphoma-2/Bcl-2-associated X protein and the increased expression of PDE4B and PDE4D in the cerebral cortex and hippocampus of AD mice. Finally, roflumilast reversed the decreased levels of cyclic AMP (cAMP) and expression of phosphorylated cAMP response element-binding protein and brain derived neurotrophic factor in AD mice. CONCLUSIONS: Together, these results suggest that roflumilast not only improves learning and memory but also attenuates depression-like behavior in AD mice, likely via PDE4B/PDE4D-mediated cAMP/cAMP response element-binding protein/brain derived neurotrophic factor signaling. Roflumilast can be a therapeutic agent for AD, in particular the comorbidity of memory loss and depression.

Combination of PhI(OAc)2 and 2-Nitropropane as the Source of Methyl Radical in Room-Temperature Metal-Free Oxidative Decarboxylation/Cyclization: Construction of 6-Methyl Phenanthridines and 1-Methyl Isoquinolines.

A room-temperature metal-free method for generating highly unstable methyl radical was realized from the combination of PhI(OAc)2 and 2-nitropropane, which provides an efficient approach to methylated phenanthridines and isoquinolines. The strategy was also extended to the generation of other alkyl radicals and a concise synthesis of Roxadustat.

A Scan of Obesogenic Environments and a Spatial Inference of Obesity Prevalence in Chinese Children and Adolescents: Based on the Chinese Health and Nutrition Survey 2011 Data.

OBJECTIVE: To identify the characteristics of Chinese obesogenic environments at a provincial level, infer a spatial distribution map of obesity prevalence in 31 provinces, and provide a foundation for development of policy to reduce obesity in children and adolescents. METHODS: After scanning obesity data on subjects aged 7-17 years from 12 provinces in the China Health and Nutrition Survey 2011 and environmental data on 31 provinces from the China Statistical Yearbook 2011 and other sources, we selected 12 predictors. We used the 12 surveyed provinces as a training sample to fit an analytical model with partial least squares regression and prioritized the 12 predictors using variable importance in projection. We also fitted a predictive model with Bayesian analysis. RESULTS: We identified characteristics of obesogenic environments. We fitted the predictive model with a deviance information criterion of 61.96 and with statistically significant (P < 0.05) parameter estimates of intercept [95% confidence interval (CI): 329.10, 963.11], log(oil) (CI: 13.11, 20.30), log(GDP) (CI: 3.05, 6.93), log(media) (CI: -234.95, -89.61), and log(washing-machine) (CI: 0.92, 5.07). The total inferred average obesity prevalence among those aged 7-17 was 9.69% in 31 Chinese provinces in 2011. We also found obvious clustering in occurrences of obesity in northern and eastern provinces in the predicted map. CONCLUSION: Given complexity of obesity in children and adolescents, concerted efforts are needed to reduce consumption of edible oils, increase consumption of vegetables, and strengthen nutrition, health, and physical activity education in Chinese schools. The northern and eastern regions are the key areas requiring intervention.

Therapeutic Effects of 6-Gingerol, 8-Gingerol, and 10-Gingerol on Dextran Sulfate Sodium-Induced Acute Ulcerative Colitis in Rats.

Ulcerative colitis is one of the most common types of inflammatory bowel disease and is multifactorial and relapsing. 6-Gingerol, a component of gingerols extracted from ginger (Zingiber officinale), has been reported to improve ulcerative colitis. The present study aims to investigate the therapeutic efficacy of two analogous forms of 6-gingerol, 8-gingerol, and 10-gingerol, on ulcerative colitis. Colitis was induced in rats through consumption of 5% (w/v) dextran sulfate sodium drinking water for 7 consecutive days. 6-Gingerol, 8-gingerol, and 10-gingerol were then given intraperitoneally at doses of 30 mg kg-1  d-1 for another 7 days, respectively. Body weight change, disease activity index, inflammatory cytokines, and oxidative stress indices were measured, and the colonic tissue injuries were assessed macroscopically and histopathologically. Results showed that all three gingerols attenuated colitic symptoms evoked by dextran sulfate sodium, significantly elevated superoxide dismutase activity, decreased malondialdehyde levels and myeloperoxidase activity in the colon tissue, and markedly reduced the content of tumor necrosis factor alpha and Interleukin 1 beta in the serum. Histological observations showed that all three gingerols obviously accelerated mucosal damage healing. It is concluded that 6-gingerol, 8-gingerol, and 10-gingerol, the three analogues, have a strong and relatively equal efficacy in the treatment of colitis. Copyright © 2017 John Wiley & Sons, Ltd.

Gender difference in the association between food away-from-home consumption and body weight outcomes among Chinese adults.

OBJECTIVE: The present study aimed to explore the associations between food away-from-home (FAFH) consumption and body weight outcomes among Chinese adults. DESIGN: FAFH was defined as food prepared at restaurants and the percentage of energy from FAFH was calculated. Measured BMI and waist circumference (WC) were used as body weight outcomes. Quantile regression models for BMI and WC were performed separately by gender. SETTING: Information on demographic, socio-economic, diet and health parameters at individual, household and community levels was collected in twelve provinces of China. SUBJECTS: A cross-sectional sample of 7738 non-pregnant individuals aged 18-60 years from the China Health and Nutrition Survey 2011 was analysed. RESULTS: For males, quantile regression models showed that percentage of energy from FAFH was associated with an increase in BMI of 0·01, 0·01, 0·01, 0·02, 0·02 and 0·03 kg/m2 at the 5th, 25th, 50th, 75th, 90th and 95th quantile, and an increase in WC of 0·04, 0·06, 0·06, 0·04, 0·06, 0·05 and 0·07 cm at the 5th, 10th, 25th, 50th, 75th, 90th and 95th quantile. For females, percentage of energy from FAFH was associated with 0·01, 0·01, 0·01 and 0·02 kg/m2 increase in BMI at the 10th, 25th, 90th and 95th quantile, and with 0·05, 0·04, 0·03 and 0·03 cm increase in WC at the 5th, 10th, 25th and 75th quantile. CONCLUSIONS: Our findings suggest that FAFH consumption is relatively more important for BMI and WC among males rather than females in China. Public health initiatives are needed to encourage Chinese adults to make healthy food choices when eating out.

The checkpoint 1 kinase inhibitor LY2603618 induces cell cycle arrest, DNA damage response and autophagy in cancer cells.

Chemotherapy- or radiotherapy-induced DNA damage activates the Chk1-dependent DNA damage response (DDR) and cell cycle checkpoints to facilitate cell survival. Numerous attempts have been made to identify specific Chk1 inhibitors to enhance the efficiency of chemotherapy or radiotherapy. In this study, we investigated the molecular mechanisms underlying the antitumor activity of LY2603618, a potent and selective small molecule inhibitor of Chk1 protein kinase, in human lung cancer cells. Treatment of cancer cells with LY2603618 caused cell cycle arrest in the G2/M phase. A marked induction of DDR, including the phosphorylation of ATM, Chk2, p53 and histone H2AX, was observed after LY2603618 treatment. LY2603618 inhibited Chk1 autophosphorylation (S296 Chk1) and increased DNA damage-mediated Chk1 phosphorylation (S345 Chk1). In addition, LY2603618-treated lung cancer cells transitioned from LC3-I to LC3-II, a hallmark of autophagy. Blocking autophagy with chloroquine (CQ) further enhanced LY2603618's inhibitory effect on cell viability/proliferation. LY2603618 also significantly increased p38 and c-Jun N-terminal kinase (JNK) phosphorylation. Pretreatment with the JNK inhibitor reduced cleavage of caspase-3 and PARP levels in LY2603618-treated cells. These results suggest the following: (i) the biological consequences of LY2603618 in lung cancer cells is associated with both inhibition of Chk1 phosphorylation on S296 and activation of the DNA damage response network; and (ii) the anticancer property of LY2603618 might be increased by inhibiting autophagy.

[Trend in meat consumption patterns among Chinese children in nine provinces(autonomous region) aged 6 to 17 years between 1991 and 2011].

OBJECTIVE: To examine the trend in meat consumption patterns between 1991 and 2011 in Chinese children in nine provinces(autonomous region) aged 6 to 17 years. METHODS: A multistage, random cluster sampling process was used to investigate 2720, 2702, 2525, 2405, 1509, 1238, 1085, and 936 children and adolescents aged 6-17 years in 1991, 1993, 1997, 2000, 2004, 2006, 2009 and 2011 respectively in 9 provinces (autonomous region) in China. Their consecutive 3 d 24 h dietary recall data were analyzed to compare meat intake pattern in children and adolescents with different characteristics and different years. RESULTS: The consumption rate increased from 60.9% (1657/2720) in 1991 to 87.2% (816/936) in 2011 for livestock meat (χ(2) = 458.23, P < 0.01), from 9.4% (257/2720) to 33.3% (312/936) for poultry (χ(2) = 446.07, P < 0.01) and from 27.3% (743/2720) to 40.6% (380/936) for seafood (χ(2) = 89.89, P < 0.01). The median of total meat intake increased from 47.4 g/d in 1991 to 100.0 g/d in 2011 (χ(2) = 516.77, P < 0.01), poultry intake from 33.3 g/d to 60.0 g/d (χ(2) = 420.13, P < 0.01), pork intake from 26.7 g/d to 50.0 g/d (χ(2) = 380.50, P < 0.01). The percentage of children whose livestock meat and poultry intakes higher than the recommended amount increased from 32.9% (896/2720) in 1991 to 59.8% (560/936) in 2011 (χ(2) = 392.97, P < 0.01); the percentage of children whose seafood intakes meeting the recommended amount increased from 6.9% (187/2720) in 1991 to 8.8% (82/936) in 2011 (χ(2) = 21.52, P < 0.01). The consumption rates of livestock meat in urban and rural children increased from 81.2% (536/660) and 54.4% (1121/2060) in 1991 to 94.7% (234/247) (χ(2) = 38.34, P < 0.01) and 84.5% (582/689) (χ(2) = 429.26, P < 0.01) in 2011. The intakes of livestock meat in rural children increased from 16.7 g/d in 1991 to 56.7 g/d in 2011 (χ(2) = 472.46, P < 0.01). CONCLUSION: The overall pattern of meat consumption in Chinese children in nine provinces(autonomous region) was unreasonable between 1991 and 2011. There was a significant improvement in meat consumption in rural children over time.

Corrigendum: Essential role of microglia in the fast antidepressant action of ketamine and hypidone hydrochloride (YL-0919).

[This corrects the article DOI: 10.3389/fphar.2023.1122541.].

Essential role of microglia in the fast antidepressant action of ketamine and hypidone hydrochloride (YL-0919).

Introduction: Intracerebral microglia play a vital role in mediating central immune response, neuronal repair and synaptic pruning, but its precise role and mechanism in fast action of antidepressants have remained unknown. In this study, we identified that the microglia contributed to the rapid action of antidepressants ketamine and YL-0919. Methods: The depletion of microglia was achieved with the diet containing the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 in mice. The tail suspension test (TST), forced swimming test (FST) and novelty suppressed feeding test (NSFT) were employed to evaluate the rapid acting antidepressant behavior of ketamine and YL-0919 in the microglia depletion model. The number of microglia in the prefrontal cortex (PFC) was assayed by the immunofluorescence staining. The expressions of synaptic proteins (synapsin-1, PSD-95, GluA1) and brain-derived neurotrophic factor (BDNF) in the PFC were tested by Western blot. Results: The immobility duration in FST and the latency to feed in NSFT were shortened 24 h after an intraperitoneal (i.p.) injection of ketamine (10 mg/kg). The microglial depletion of PLX3397 blocked the rapid antidepressant-like effect of ketamine in mice. In addition, the immobility time in TST and FST as well as latency to feed in NSFT were reduced 24 h after the intragastric (i.g.) administration of YL-0919 (2.5 mg/kg), and the rapid antidepressant effect of YL-0919 was also blocked by the microglial depletion using PLX5622. About 92% of microglia in the prefrontal cortex was depleted in PLX5622 diet-fed mice, while both ketamine and YL-0919 promoted proliferation on the remaining microglia. YL-0919 significantly increased the protein expressions of synapsin-1, PSD-95, GluA1 and BDNF in the PFC, all of which could be blocked by PLX5622. Conclusion: These results suggested the microglia underlying the rapid antidepressant-like effect of ketamine and YL-0919, and microglia would likely constitute in the rapid enhancing impact of synaptic plasticity in the prefrontal cortex by YL-0919.

[Trend of energy intake among Chinese children and adolescents in nine provinces from 1989 to 2009].

OBJECTIVE: To examine the trends of energy intake among Chinese children and adolescents in nine provinces from 1989 to 2009. METHOD: Stratified multi-stage cluster sampling method was used to recruit 488, 2807, 2802, 2580, 2520, 1604, 1305 and 1159 children and adolescents aged 6 - 17 years in each year of 1989, 1991, 1993, 1997, 2000, 2004, 2006 and 2009 in 9 provinces. The descriptive analyses were carried out for three days 24-h dietary recall data to compare energy intake by year and demographic characteristics. RESULTS: The median of dietary energy intake among Chinese children and adolescents aged 6 - 17 years in 1989, 1991, 1993, 1997, 2000, 2004, 2006 and 2009 were 6645.7, 8314.8, 7849.3, 8115.0, 7970.5, 7598.0, 7345.0 and 7051.9 kJ/d (χ(2) = 239.75, P < 0.01), respectively. In 2009, children and adolescents from city (7820.4 kJ/d) and county (7356.0 kJ/d) consumed more energy than that from suburb (7168.2 kJ/d) and village (6863.5 kJ/d) (χ(2) = 8.00, P < 0.05). Cereal was the main food source of energy intake. In 2009, the percentage of energy intake from cereal was 44.0%, 45.6%, 52.9% and 61.0% (χ(2) = 36.75, P < 0.01)for city, suburb, county and village respectively. The percentage of population with > 30% of energy intake from dietary fat increased yearly and that with more than 60% of energy from carbohydrate decreased, from 25.4% (124/488) and 54.1% (264/488) in 1989 to 58.1% (637/1159) and 15.9% (184/1159) (χ(2) values were 811.24, 919.35 respectively;both P values < 0.05) in 2009. The percentage of children and adolescents whose energy intake was more than 80% recommended nutrient intake (RNI) declined from 60.2% (294/488) in 1989 to 47.8% (554/1159) in 2009(χ(2) = 227.66, P < 0.05). CONCLUSION: The current study demonstrated that energy intake of Chinese children and adolescents increased at early stage and then declined in the recent years. Average energy intake was higher in city and county than suburb and village.

[Trend in dietary vitamin C intake among Chinese children and adolescents between 1991 and 2009].

OBJECTIVE: To examine status and trend in dietary vitamin C intake between 1991 and 2009 in Chinese children and adolescents aged 6 to 17 years. METHODS: A stratified multistage, random cluster sampling process was used to investigate 2716, 2691, 2507, 2358, 1490, 1218 and 1073 children and adolescents aged 6 - 17 years in 1991, 1993, 1997, 2000, 2004, 2006 and 2009 respectively in 9 provinces. Their consecutive 3 d 24 h dietary recall data were analyzed to compare vitamin C intake in children and adolescents with different characteristics and different years. RESULTS: The median of dietary vitamin C intake in Chinese children and adolescents decreased from 69.7 mg/d in 1991 to 53.4 mg/d in 2009 (χ(2) = 188.1, P < 0.01). Vitamin C intake of rural children and adolescents decreased from 73.7 mg/d in 1991 to 52.5 mg/d in 2009 (χ(2) = 96.7, P < 0.01); vitamin C intake of children and adolescents in the low-income household decreased from 74.3 mg/d in 1991 to 47.5 mg/d in 2009 (χ(2) = 172.9, P < 0.01). The percentage of children and adolescents whose vitamin C intake equal or higher than recommended nutrient intake of vitamin C decreased from 35.9% (974/2716) in 1991 to 18.5% (198/1073) in 2009 (χ(2) = 284.7, P < 0.01). CONCLUSION: There was a decreased trend in dietary vitamin C in Chinese children and adolescents during the past two decades. The children and adolescents of low-income household in rural areas may pose a higher risk of inadequate vitamin C intake.

[Trends in dietary protein intake among Chinese children and adolescent between 1991 and 2009].

OBJECTIVE: To examine dietary protein intake and its trend between 1991 and 2009 among Chinese children and adolescents aged 6 to 17 years. METHODS: Consecutive 3 d-24 hr Dietary Recall and household income data of 14 053 children from the seven waves of the China Health and Nutrition Survey (CHNS), 1991, 1993, 1997, 2000, 2004, 2006 and 2009 were used to describe long-term changes in dietary protein intake, percentage energy, and food sources. RESULTS: The median of dietary protein intake of Chinese children and adolescents decreased from 60.0 g/d in 1991 to 52.6 g/d in 2009 (χ² = 109.0, P < 0.01). The dietary protein intake among children in rural areas and in low-income households decreased 8.8 g/d (χ² = 74.8, P < 0.01) and 9.8 g/d (χ² = 100.5, P < 0.01) respectively. The percentage of total energy intake from protein was 11.3%-13.0%. The percentage of protein intake equal or higher than Recommended Nutrient Intake of protein decreased from 29.5% in 1991 to 19.2% in 2009 (χ² = 259.6, P < 0.01). Furthermore, the proportion of high-quality dietary protein increased rapidly. The percentage of animal protein increased from 12.3% in 1991 to 32.2% in 2009 (χ² = 750.3, P < 0.01), while no big increase in soybean protein (lower than 5.0%). CONCLUSION: There is a decreasing trend in dietary protein intake among Chinese children from 1991 to 2009. The high-quality protein intake was improved but we should be concerned about the high proportion of animal protein. The children living in low-income households and in rural areas may be at risk of inadequate dietary protein.

PKC-ζ Aggravates Doxorubicin-Induced Cardiotoxicity by Inhibiting Wnt/ß-Catenin Signaling.

Doxorubicin (Dox) is a chemotherapeutic drug used to treat a wide range of cancers, but its clinical application is limited due to its cardiotoxicity. Protein kinase C-ζ (PKC-ζ) is a serine/threonine kinase belonging to atypical protein kinase C (PKC) subfamily, and is activated by its phosphorylation. We and others have reported that PKC-ζ induced cardiac hypertrophy by activating the inflammatory signaling pathway. This study focused on whether PKC-ζ played an important role in Dox-induced cardiotoxicity. We found that PKC-ζ phosphorylation was increased by Dox treatment in vivo and in vitro. PKC-ζ overexpression exacerbated Dox-induced cardiotoxicity. Conversely, knockdown of PKC-ζ by siRNA relieved Dox-induced cardiotoxicity. Similar results were observed when PKC-ζ enzyme activity was inhibited by its pseudosubstrate inhibitor, Myristoylated. PKC-ζ interacted with ß-catenin and inhibited Wnt/ß-catenin signaling pathway. Activation of Wnt/ß-catenin signaling by LiCl protected against Dox-induced cardiotoxicity. The Wnt/ß-catenin inhibitor XAV-939 aggravated Dox-caused decline of ß-catenin and cardiomyocyte apoptosis and mitochondrial damage. Moreover, activation of Wnt/ß-catenin suppressed aggravation of Dox-induced cardiotoxicity due to PKC-ζ overexpression. Taken together, our study revealed that inhibition of PKC-ζ activity was a potential cardioprotective approach to preventing Dox-induced cardiac injury.

A novel phosphodiesterase 9A inhibitor LW33 protects against ischemic stroke through the cGMP/PKG/CREB pathway.

BACKGROUND: Ischemic stroke is one of the leading causes of mortality worldwide. The available treatments are not effective. Phosphodiesterase 9A (PDE9A) is an intracellular cyclic guanosine monophosphate (cGMP) hydrolase considered to be a promising therapeutic target for brain diseases. This study explored neuroprotective effects and the underlying mechanism of LW33, a novel PDE9A inhibitor, on ischemic stroke in vitro and in vivo. METHODS: A middle cerebral artery occlusion (MCAO) model was established in adult male Sprague-Dawley rats and an oxygen-glucose deprivation/reoxygenation (OGD/R) model was established in human SH-SY5Y cells to mimic ischemia-reperfusion injury in vitro. RESULTS: LW33 increased cell viability, reduced lactate dehydrogenase activity, and OGD/R-induced apoptosis of SH-SY5Y cells. The protective effects of LW33 against stroke occurred in the recovery phase. LW33 administration significantly reduced cerebral infarction volume in MCAO rats, without causing significant deformation or necrosis of neurons in the cortex. LW33 also improved learning and cognitive dysfunction and reduced other pathological changes in MCAO rats in the recovery period. Moreover, LW33 stimulated the cGMP/PKG/CREB pathway and up-regulated the expression of the apoptosis-related proteins, and this effect was reversed by KT5823 treatment. CONCLUSION: LW33 inhibited cell apoptosis and promoted neuronal repair to alleviate OGD/R and MCAO induced pathological alterations via the cGMP/PKG/CREB pathway, indicating that LW33 may be a promising therapeutic target for ischemic stroke.

Inhibition of phosphodiesterase-4 in the spinal dorsal horn ameliorates neuropathic pain via cAMP-cytokine-Cx43 signaling in mice.

BACKGROUND: The spinal phosphodiesterase-4 (PDE4) plays an important role in chronic pain. Inhibition of PDE4, an enzyme catalyzing the hydrolysis of cyclic adenosine monophosphate AMP (cAMP), produces potent antinociceptive activity. However, the antinociceptive mechanism remains largely unknown. Connexin43 (Cx43), a gap junction protein, has been shown to be involved in controlling pain transduction at the spinal level; restoration of Cx43 expression in spinal astrocytes to the normal levels reduces nerve injury-induced pain. Here, we evaluate the novel mechanisms involving spinal cAMP-Cx43 signaling by which PDE4 inhibitors produce antinociceptive activity. METHODS: First, we determined the effect of PDE4 inhibitors rolipram and roflumilast on partial sciatic nerve ligation (PSNL)-induced mechanical hypersensitivity. Next, we observed the role of cAMP-Cx43 signaling in the effect of PDE4 inhibitors on PSNL-induced mechanical hypersensitivity. RESULTS: Single or repeated, intraperitoneal or intrathecal administration of rolipram or roflumilast significantly reduced mechanical hypersensitivity in mice following PSNL. In addition, repeated intrathecal treatment with either of PDE4 inhibitors reduced PSNL-induced downregulation of cAMP and Cx43, and upregulation of proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1ß. Furthermore, the antinociceptive effects of PDE4 inhibitors were attenuated by the protein kinase A (PKA) inhibitor H89, TNF-α, or Cx43 antagonist carbenoxolone. Finally, PSNL-induced upregulation of PDE4B and PDE4D, especially the PDE4B subtype, was reduced by treatment with either of the PDE4 inhibitors. CONCLUSIONS: The results suggest that the antinociceptive effect of PDE4 inhibitors is contributed by increasing Cx43 expression via cAMP-PKA-cytokine signaling in the spinal dorsal horn.

[The status of dietary sodium intake of Chinese population in nine provinces (autonomous region) from 1991 to 2006].

OBJECTIVE: To analyze the status of dietary sodium intake of 18 - 65 years old Chinese people in nine provinces (autonomous region) in 1991 and 2006. METHODS: In 1991 and 2006, China Health and Nutrition Survey was carried out in nine provinces, including Liaoning, Heilongjiang, Shandong, Jiangsu, Henan, Hunan, Hubei, Guangxi and Guizhou, Subjects were selected by multi-stage stratified cluster random sampling method from 18 - 65 years old people and 8235 subjects in 1991 and 7788 subjects in 2006. Sodium intake analysis was conducted across gender, regions and rural(urban) residences. RESULTS: On average, sodium intake decreased from (6750.6 ± 3771.5) mg/d in 1991 to (4949.7 ± 2829.4) mg/d in 2006 (Z = -35.5, P < 0.01) among the 18 - 65 years old people. In 1991 and 2006, the main sources of dietary sodium were salt, soy sauce and vegetable. In 1991, the proportion were 79.6% ((5375.6 ± 3532) mg/d), 8.7% ((586.7 ± 721.7) mg/d) and 7.5% ((506.9 ± 906.1) mg/d), respectively. In 2006, the proportion were 71.5% ((3539.8 ± 2545) mg/d), 8.3% ((410.7 ± 547.9) mg/d) and 6.2% ((304.6 ± 610.7) mg/d), respectively. CONCLUSIONS: Among 18 - 65 years old residents, sodium intake in 2006 was significantly lower than that in 1991, but still far beyond the 2200 mg/d of adequate intake level (2200 mg/d). The major source of sodium intake in Chinese diet was condiments.

[The status and trend of cereal consumption among Chinese adults in nine provinces (municipality) from 1989 to 2006].

OBJECTIVE: To explore the status and trend of cereal consumption among Chinese adults aged 18 to 59 years in nine provinces (municipality) from 1989 to 2006. METHODS: The survey data were collected by consecutive 3 d 24 h dietary recall method in 1989, 1991, 1993, 1997, 2000, 2004 and 2006 China Health and Nutrition Survey Project. The subjects aged 18-59 years with complete information on dietary survey were included. The sample number of the subjects were 5978, 7566, 7492, 7738, 8439, 7484 and 7157 in the 7 round surveys from 1989 to 2006, respectively. The trends of their cereal consuming rate and daily intake were analyzed by year, gender, age and regions. RESULTS: The cereal intake of 18 - 59 years old Chinese adults in 9 provinces (municipality) decreased from 522.3 g/d in 1989 to 431.9 g/d in 2006 (χ(2) = 2421.76, P < 0.01). The cereal intake of males decreased from 545.6 g/d in 1989 to 471.6 g/d in 2006 (χ(2) = 861.21, P < 0.01) and females decreased from 500.3 g/d in 1989 to 395.5 g/d in 2006 (χ(2) = 1844.13, P < 0.01). Compared with 1989, the average cereal consumption were reduced to 104.8, 134.4, 103.3 and 98.2 g in the suburban, female, 18 to 29 years old age group and level of education for college and above separately in 2006. The rice consuming rate among 18 - 59 year-old residents increased from 79.9% (4776/5978) in 1989 to 87.3% (6248/7157) (Z = 18.45, P < 0.01) in 2006, the wheat consuming rate increased from 63.3% (3784/5978) in 1989 to 80.2% (5740/7157) (Z = 27.28, P < 0.01) in 2006. CONCLUSION: The present study indicated that there was a decreasing trend of cereal intake among Chinese adults aged 18 - 59 years in 9 provinces (municipality). In the stratified groups, cereal intake in groups of female, suburb, aged 18 - 59 years and higher educational level decreased significantly.