STAT3-specific nanocarrier for shRNA/drug dual delivery and tumor synergistic therapy.

Non-small cell lung cancer (NSCLC) is a major disease with high incidence, low survival rate and prone to develop drug resistance to chemotherapy. The mechanism of secondary drug resistance in NSCLC chemotherapy is very complex, and studies have shown that the abnormal activation of STAT3 (Signal Transducer and Activator of Transcription 3) plays an important role in it. In this study, the pGPU6/GFP/Neo STAT3-shRNA recombinant plasmid was constructed with STAT3 as the precise target. By modifying hydrophilic and hydrophobic blocks onto chitosan, a multifunctional vitamin E succinate-chitosan-polyethylene glycol monomethyl ether histidine (VES-CTS-mPEG-His) micelles were synthesized. The micelles could encapsulate hydrophobic drug doxorubicin through self-assembly, and load the recombinant pGPU6/GFP/Neo STAT3-shRNA (pDNA) through positive and negative charges to form dual-loaded nanoparticles DOX/VCPH/pDNA. The co-delivery and synergistic effect of DOX and pDNA could up-regulate the expression of PTEN (Phosphatase and Tensin Homolog), down-regulate the expression of CD31, and induce apoptosis of tumor cells. The results of precision targeted therapy showed that DOX/VCPH/pDNA could significantly down-regulate the expression level of STAT3 protein, further enhancing the efficacy of chemotherapy. Through this study, precision personalized treatment of NSCLC could be effectively achieved, reversing its resistance to chemotherapy drugs, and providing new strategies for the treatment of drug-resistant NSCLC.

Impact of painful physical symptoms on first-episode major depressive disorder in adults with subthreshold depressive symptoms: A prospective cohort study.

OBJECTIVE: To investigate the impact of baseline painful physical symptoms (PPS) on subsequent first-episode major depressive disorder (MDD) in adults with subthreshold depressive symptoms, including subgroup analyses to assess whether the associations differ in individuals with and without physical diseases. METHODS: A total of 2343 adults with subthreshold depressive symptoms were recruited at 34 primary health care centers. PPS were measured at baseline. First-episode MDD during follow-up was diagnosed by professional psychiatrists using the Mini-International Neuropsychiatric Interview. RESULTS: Baseline PPS showed independent impacts on first-episode MDD in adults with subthreshold depressive symptoms without physical diseases, but not in those with physical diseases. A non-linear association (P < 0.001) was observed between PPS burden and the risk of first-episode MDD. The HRs for first-episode MDD exhibited a rapidly increasing trend between PPS burden scores of 10-16, and maintained consistently high when scores exceeded 16. The analyses for specific PPS revealed that headache, neck pain, and heart or chest pain were independently associated with first-episode MDD in participants without physical diseases, the HRs were 1.57 (1.15-2.36), 1.53 (1.02-2.30), and 1.69 (1.14-2.50), respectively. Further network analysis demonstrated that heart or chest pain serves as a bridge symptom among the seven specific PPS and first-episode MDD in those without physical diseases. CONCLUSION: PPS burden and heart or chest pain may be significant indicators for first-episode MDD in adults with subthreshold depressive symptoms without physical diseases. Future studies should investigate whether interventions targeting PPS can prevent episode MDD in this subthreshold population.

Mediation and interaction of problematic internet use in the relationship between sexual minority status and depressive symptoms: Gender-based analysis.

BACKGROUND: Previous studies have demonstrated that sexual minorities are at a higher risk of experiencing depressive symptoms. However, few prior investigations have examined the potential mechanisms involved. This study aimed to employ the four-way decomposition approach that integrates the analysis of mediation and interaction to investigate the potential role of problematic internet use between sexual orientation and depressive symptoms. METHODS: The participants were recruited through a multi-stage, stratified cluster, and random sampling method in China. Students who identified as "gay or lesbian" and "bisexual" were defined as "sexual minorities". The Young's Internet Addiction Test (IAT) was used to evaluate problematic internet use. The Center for Epidemiologic Studies Depression Scale (CESD-20) was used to evaluate depressive symptoms. RESULTS: A total of 59,859 adolescents were included in this study, with 30,180 (53.25 %) boys and 29,679 (46.75 %) girls. Of these, 7263 (12.13 %) were identified as sexual minorities. Gender differences were observed in the association between sexual orientation, problematic internet use, and depressive symptoms. The mediating effect of problematic internet use was 28.80 % for boys and 36.84 % for girls, respectively. The interaction effect between problematic internet use and sexual minority status on depressive symptoms was 21.19 % and 9.65 % for boys and girls, respectively. LIMITATIONS: The current study was limited by the cross-sectional design. CONCLUSION: These findings suggest that prevention and intervention programs aimed at improving mental health outcomes among sexual minority adolescents should prioritize considering the impact of problematic internet use and potential gender differences.

Association between lipocalin-2 and mild cognitive impairment or dementia: A systematic review and meta-analysis of population-based evidence.

BACKGROUND: The associations between lipocalin-2 (LCN2) with mild cognitive impairment (MCI) and dementia have gained growing interest. However, population-based studies have yielded inconsistent findings. Therefore, we conducted this essential systematic review and meta-analysis to analyze and summarize the existing population-based evidence. METHODS: PubMed, EMBASE, and Web of Science were systematically searched until Mar 18, 2022. Meta-analysis was performed to generate the standard mean difference (SMD) of peripheral blood and cerebrospinal fluid (CSF) LCN2. A qualitative review was performed to summarize the evidence from postmortem brain tissue studies. RESULTS: In peripheral blood, the overall pooled results showed no significant difference in LCN2 across Alzheimer's disease (AD), MCI and control groups. Further subgroup analysis revealed higher serum LCN2 levels in AD compared to controls (SMD =1.28 [0.44;2.13], p = 0.003), while the difference remained insignificant in plasma (SMD =0.04 [-0.82;0.90], p = 0.931). Besides, peripheral blood LCN2 were higher in AD when age difference between AD and controls ≥ 4 years (SMD =1.21 [0.37;2.06], p = 0.005). In CSF, no differences were found in LCN2 across groups of AD, MCI and controls. However, CSF LCN2 was higher in vascular dementia (VaD) compared to controls (SMD =1.02 [0.17;1.87], p = 0.018), as well as compared to AD (SMD =1.19 [0.58;1.80], p < 0.001). Qualitative analysis supported that LCN2 was increased in the brain tissue of AD-related areas, especially in astrocytes and microglia; while LCN2 increased in infarct-related brain areas and over-expressed in astrocytes and macrophages in mixed dementia (MD). CONCLUSION: The difference in peripheral blood LCN2 between AD and controls may be affected by the type of biofluid and age. No differences were found in CSF LCN2 across AD, MCI and controls groups. In contrast, CSF LCN2 was elevated in VaD patients. Moreover, LCN2 was increased in AD-related brain areas and cells in AD, while in infarcts-related brain areas and cells in MD.

[Source Profiles of Industrial Emission-Based VOCs in Chengdu].

The volatile organic compound (VOC) emission characteristics of various production procedures were analyzed through GC-MS after the emissions of typical enterprises such as automobile manufacturing, petrochemical, and other industries had been sampled with SUMMA canisters. Each production procedure in the automobile manufacturing and petrochemical industries was considered. The results showed that each automobile manufacturing procedure had its own dominant species, and alkanes (32%) and aromatics (35%) were the main emission species of coating spraying. The emission characteristics of furniture manufacturing were highly correlated with the raw materials, and the VOC emission species were mainly composed of aromatics (50%) and oxygenated VOCs (OVOCs) (38%). As for the petrochemical industry, VOC concentrations in various process plant areas ranged from 49 µg·m-3 to 1387 µg·m-3. As the main products of the refining area were C5-C9 gasoline and benzene series, whereas comparatively more solvents were used in the chemical area, which would generate alkene products, VOC concentrations greatly differed in the various process plant areas. In terms of electronic manufacturing, OVOCs were the main emission species, accounting for more than 50% of total VOCs. Alkanes and OVOCs were the main contributors to VOC emissions in shoemaking, accounting for 52% and 36% on average, respectively, which was strongly related to the species of the used solvents. The VOC emission species of automobile manufacturing were quite different, predominantly including n-dodecane and 2-butanone. The emission species of furniture manufacturing mainly included styrene, ethyl acetate, m/p-xylene, etc., which are typical species of coatings and diluents. As for the differences in the emission species of process plant areas in the petrochemical industry, styrene was the main species in the refining area, 1,3-butadiene in the chemical area, C3-C5 alkanes in the storage area, and C6-C8 alkanes in the wastewater treatment area. The main emission species of electronic manufacturing were ethanol, acetone, and other aldehyde ketone species. The emission species of shoemaking enterprises are mainly C5 and C6 alkanes. According to the results of ozone formation potential (OFP), alkenes and aromatics were the main VOC emission species that contribute significantly to the OFP in the automobile manufacturing and petrochemical industries, with relatively high pollution source reaction activity. The results showed that the emission ratio (17%-96%) and OFP contributions of OVOCs were significant in various industries. Therefore, for VOC emission control, in addition to focusing on the control of aromatics and alkenes, attention should also be paid to OVOCs.

[Source Profiles of VOCs Associated with Typical Industrial Processes in Chengdu].

The characteristics of volatile organic compound (VOCs) species from various production procedures of wood-based panel production and other industrial processes in Chengdu were analyzed through gas chromatography-mass spectrometry (GC-MS) and other methods specified in national standards after the emissions of typical enterprises of wood-based panel production, pharmaceutical manufacturing, chemical production and other industrial processes in Chengdu had been sampled using sampling bottles and SUMMA canisters. Generally, the process of wood-based panel production includes glue making, glue mixing, sorting, and hot pressing, whereas the process of pharmaceutical manufacturing includes workshop production and wastewater treatment. The results showed that the main contribution species of VOCs in wood-based panel production and pharmaceutical manufacturing is oxygenated VOCs (OVOCs), accounting for more than 50% of the total VOCs emitted. The species from organized and unorganized emissions of formaldehyde manufacturing differed significantly. The main species of organized emissions was OVOCs, and that of unorganized emissions was halohydrocarbons. Emissions of VOCs from coating manufacturing were strongly correlated with the raw materials, and the corresponding emission species were composed mainly of aromatics and OVOCs. Except for glue mixing, the main species of VOCs in other process procedures of wood-based panel production was formaldehyde, with emission proportion of more than 50%. The primary species of VOCs in various processes of pharmaceutical manufacturing was ethanol; however 1,4-dioxane, ethyl acetate, and toluene were also important species. Moreover, the main VOCs from formaldehyde manufacturing were composed mainly of acetone and ethanol, and those of coating manufacturing were aromatic hydrocarbons such as p-xylene. The ozone formation potential was to characterize the reactivity of pollution sources in VOCs from wood-based panel production, pharmaceutical manufacturing, and chemical production. The results showed that the species of VOCs in different industries contributed similarly to the reactivity and that these species were mainly high-activity species such as formaldehyde, ethanol, and other OVOCs as well as some aromatic hydrocarbons. Therefore, supervision and regulation of enterprises of industrial processes is required with a focus on species with relatively large ozone formation potential. In addition, it is necessary to analyze the emission characteristics and chemical mechanism of various industries and to control O3 generation from the sources.

[Speciated VOCs Emission Inventory and Ozone Formation Potential in Sichuan Province].

Based on the measured data in the literature, VOCs (volatile organic compounds) source profiles were revised and reconstructed without OVOCs (oxygenated volatile organic compounds) species to obtain the normalized VOCs source profiles. Using the 2015 Sichuan emission inventory, source profiles based on the 1 km×1 km gridded speciated VOCs emission inventory were developed, and the ozone formation potentials of the species were estimated to assess the environmental impact on ozone formation. The established VOCs source profile database consists of 45 source profiles and 519 species. Since the source profiles were established based on the revision and reconstruction of pollution sources, such as biomass burning and transportation, that are rich in OVOCs, the source profile database is better applicable to establishing the speciated VOCs emission inventory and source apportionment. The speciated VOCs emission inventory showed that the total anthropogenic emission of VOCs in Sichuan Province was 773.8 kt, of which the emissions of alkanes, olefins, alkynes, aromatics, OVOCs, halohydrocarbons, and other VOCs accounted for 21.6%, 10.0%, 1.7%, 28.0%, 26.2%, 4.2%, and 8.3% of the total respectively. The total OFP (Ozone formation potential) was 2584.9 kt, of which the OFPs of the VOCs groups mentioned above accounted for 6.9%, 26.1%, 0.5%, 42.3%, 23.2%, 0.4%, and 0.5% respectively. The main VOCs species emitted in all cities of Sichuan Province were aromatics, OVOCs, and alkanes; however, there were some significant regional differences:transportation in Chengdu, Ya'an, Aba, Ganzi, and Liangshan made a greater contribution to VOCs emissions, with alkane emissions accounting for a higher proportion in the total VOCs emission. As a heavy industrial city, Panzhihua suffered most from emissions from industrial processes, which contain a relatively high proportion of alkanes. Solvent use in Deyang, Meishan, Suining, and Ziyang made a great contribution to the VOCs emissions, and the OVOCs emission was relatively high. Emissions of VOCs and species with relatively high OFPs in Sichuan Province were mainly distributed in the Sichuan Basin, which has a dense population and highly developed industry, as well as some areas in Liangshan and Panzhihua. The main source of m-xylene and toluene was solvent use; therefore, m-xylene and toluene were relatively concentrated in developed urban areas. In addition, biomass burning contributed greatly to the emissions of ethene and formaldehyde; therefore, ethene and formaldehyde were mainly distributed in the cultivated areas of agriculturally advanced Eastern Sichuan and Southern Sichuan.

Characterizing the composition and evolution of firework-related components in air aerosols during the Spring Festival.

To examine the impacts of fireworks, size-resolved PM samples were collected using a single-particle aerosol mass spectrometer before, during and after the Spring Festival in a megacity in Chengdu, China. Chemical composition and atmospheric behavior of urban particles were studied. Ten major single particle types were resolved with ART-2a algorithm including elemental and organic carbon (ECOC), EC, OC, levoglucosan (LEV), high molecular weight organic molecules (HOM), hard metal (HM), K rich, Na rich and SiO3-. The average OC/EC ratios decreased in the order AY (4.7) > overall (4.1) > NY (4.0) > BY period (3.6), indicating that many organic pollutants had been generated after the Spring Festival. The concentrations of many species exhibited an increasing trend during the firework period, and the SOR and NOR showed a strong increase in NY period. SOR and NOR had a slight positive relationship with fireworks activity but no obvious relationship with temperature.

[Emission Inventory and Characteristics of Anthropogenic Air Pollutant Sources in the Sichuan Province].

Based on anthropogenic source activity data and emission factors for the Sichuan Province, the 1 km×1 km-gridded atmospheric air pollutant emission inventory of 2015 was developed in combination with GIS technology and the combined "bottom-up" and "top-down" construction method. The results show that the total emission of SO2, NOx, CO, PM10, PM2.5, BC, OC, VOCs, and NH3 in Chengdu is 444.9×103, 820.0×103, 3773.1×103, 1371.6×103, 537.5×103, 28.7×103, 53.1×103, 923.6×103, and 988.0×103 t, respectively. Power plants and other industrial combustion boilers contribute more than 95% of the SO2 emissions. Mobile, fossil fuel combustion, and industrial process sources contribute 54%, 23%, and 20% of the NOx emissions, respectively. The industrial process of steel production and building materials manufacturing contribute 20% PM10 of the emissions and take up 34% PM2.5 of the emissions. Fugitive dust and road fugitive dust contributes 60% PM10 and 35% PM2.5 of the emissions, respectively. Biomass combustion contributes 33% BC and 51% OC of the emissions, respectively. The solvent use of mechanical processing, building decoration, electronic equipment manufacturing, and printing and furniture industry contribute 46% of the VOCs of the emissions. The NH3 emissions mainly orginate from the sources of livestock feeding and nitrogen fertilizers, accounting for 70% and 25% of the NH3 emissions, respectively. The spatial distribution of the emissions shows that high emissions are mainly distributed in the most densely populated, agricultural, and industrial more developed areas in Panzhihua and the Sichuan Basin. The urban agglomerations of the Chengdu Plain, represented by Chengdu, Deyang, and Mianyang, are the areas with emission concentration in the Sichuan Basin. The emissions inventory in this study has uncertainties. More fundamental studies on activity data should be conducted and the emission factors of typical emission sources should be further localized to improve the emission inventory and prevention and control of complex air pollution in the Sichuan Province and provide scientific support.

The mechanism of ascorbic acid-induced differentiation of ATDC5 chondrogenic cells.

The ATDC5 cell line exhibits a multistep process of chondrogenic differentiation analogous to that observed during endochondral bone formation. Previous investigators have induced ATDC5 cells to differentiate by exposing them to insulin at high concentrations. We have observed spontaneous differentiation of ATDC5 cells maintained in ascorbic acid-containing alpha-MEM. A comparison of the differentiation events in response to high-dose insulin vs. ascorbic acid showed similar expression patterns of key genes, including collagen II, Runx2, Sox9, Indian hedgehog, and collagen X. We took advantage of the action of ascorbic acid to examine signaling events associated with differentiation. In contrast to high-dose insulin, which downregulates both IGF-I and insulin receptors, there were only minimal changes in the abundance of these receptors during ascorbic acid-induced differentiation. Furthermore, ascorbic acid exposure was associated with ERK activation, and ERK inhibition attenuated ascorbic acid-induced differentiation. This was in contrast to the inhibitory effect of ERK activation during IGF-I-induced differentiation. Inhibition of collagen formation with a proline analog markedly attenuated the differentiating effect of ascorbic acid on ATDC5 cells. When plates were conditioned with ATDC5 cells exposed to ascorbic acid, ATDC5 cells were able to differentiate in the absence of ascorbic acid. Our results indicate that matrix formation early in the differentiation process is essential for ascorbic acid-induced ATDC5 differentiation. We conclude that ascorbic acid can promote the differentiation of ATDC5 cells by promoting the formation of collagenous matrix and that matrix formation mediates activation of the ERK signaling pathway, which promotes the differentiation program.

The effect of rapamycin on bone growth in rabbits.

mTOR is a nutrient-sensing protein kinase that regulates numerous cellular processes. Our prior studies using the mTOR inhibitor, rapamycin, indicate an important role for mTOR in chondrogenesis. We extended our observations to a physiological, in vivo model of bone growth, direct infusion of rapamycin into the proximal tibial growth plates of rabbits. Rapamycin or DMSO vehicle was infused directly into growth plates by an osmotic minipump for 8 weeks. Tibial growth was followed radiographically. At the end of the experiment, growth plates were recovered for histological analysis. Six animals were studied. No untoward effects of rapamycin infusion were found. Bone growth of limbs exposed to rapamycin was slower than control limbs, particularly during the period of most rapid growth. Histological analysis revealed that growth plate height in the rapamycin-infused limbs was reduced. Both the hypertrophic and proliferative zones were significantly smaller in the rapamycin-infused limbs. Direct infusion of rapamycin into proximal tibial growth plates decreased the size of the growth plate and inhibited overall long bone growth. Rapamycin appears to affect both the proliferative and hypertrophic zones of the tibial growth plate. Our results indicate that nutrients may exert a direct effect on long bone growth via mTOR-mediated modulation of chondrogenesis at the growth plate. and suggest that the possible inhibitory effects of rapamycin on skeletal growth warrant further attention before its use in children.

The effect of rapamycin on DNA synthesis in multiple tissues from late gestation fetal and postnatal rats.

Rapamycin is a potent antiproliferative agent that arrests cells in the G1 phase of the cell cycle through a variety of mechanisms involving the inhibition of the mammalian target of rapamycin (mTOR) pathway. The majority of normal cells in culture are sensitive to the cytostatic effects of rapamycin, whereas the growth of many malignant cells and tumors is rapamycin resistant. We had shown previously that hepatic DNA synthesis in the late gestation rat fetus is rapamycin resistant even though signaling through the mTOR/S6 kinase (S6K) pathway is attenuated. On the basis of this finding, we went on to characterize the response to rapamycin in a spectrum of tissues during late gestation and the early postnatal period in the rat. We found that rapamycin had no effect on DNA synthesis in major organs such as heart, intestine, and kidney in the fetal and early postnatal rat despite a marked attenuation in the phosphorylation of ribosomal protein S6. In contrast, the proliferation of mature hepatocytes during liver regeneration was highly sensitive to rapamycin. These data indicate that basal cellular proliferation in a wide variety of tissues is rapamycin resistant and occurs independently of mTOR/S6K signaling. Furthermore, the well-characterized effects of rapamycin in tissue culture systems are not recapitulated in the asynchronous cell proliferation that accompanies normal growth and tissue remodeling.

mTOR signaling contributes to chondrocyte differentiation.

The mammalian Target Of Rapamycin (mTOR) is a nutrient-sensing protein kinase that regulates numerous cellular processes. Fetal rat metatarsal explants were used as a physiological model to study the effect of mTOR inhibition on chondrogenesis. Insulin significantly enhanced their growth. Rapamycin significantly diminished this response to insulin through a selective effect on the hypertrophic zone. Cell proliferation (bromodeoxyuridine incorporation) was unaffected by rapamycin. Similar observations were made when rapamycin was injected to embryonic day (E) 19 fetal rats in situ. In the ATDC5 chondrogenic cell line, rapamycin inhibited proteoglycan accumulation and collagen X expression. Rapamycin decreased content of Indian Hedgehog (Ihh), a regulator of chondrocyte differentiation. Addition of Ihh to culture medium reversed the effect of rapamycin. We conclude that modulation of mTOR signaling contributes to chondrocyte differentiation, perhaps through its ability to regulate Ihh. Our findings support the hypothesis that nutrients, acting through mTOR, directly influence chondrocyte differentiation and long bone growth.

The role of insulin in chondrogenesis.

The ATDC5 chondrogenic cell line is typically induced to differentiate by exposure to insulin at high concentration (10 microg/ml, approximately 1600 nM). Differentiation can also be induced by physiological concentrations of insulin-like growth factor-I (IGF-I). Unlike previous reports, we observed a stimulation of differentiation, as measured by collagen X expression and Alcian Blue staining for proteoglycan synthesis, upon exposure to insulin at concentrations (10-50 nM) consistent with signaling via the insulin receptor. Analysis of lysates from proliferating and hypertrophic ATDC5 cells demonstrated that exposure to 50 nM insulin induced tyrosine phosphorylation of insulin receptors but not IGF-I receptors or hybrid receptors. In contrast to the potent effects of IGF-I to stimulate both ATDC5 proliferation and differentiation, insulin was not as potent as IGF-I as a proliferating agent but more selectively a differentiating agent. Consistent with this result, insulin was less potent than IGF-I in inducing activation of the Erk1/Erk2 mitogenic signaling pathway. Furthermore, Erk pathway inhibition did not enhance the differentiating effects of insulin as it does in the case of IGF-I exposure. Extending our observations to fetal rat metatarsal explants, we observed significant stimulation of bone growth by 50 nM insulin. This could be accounted for by a disproportionate stimulatory effect on growth of the hypertrophic zone. The proliferative zone was not significantly affected. Based on our results in both ATDC5 cells and metatarsal explants, we conclude that the insulin functioning through insulin receptor has a dominant effect as an inducer of chondrocyte differentiation. These results support assignment of a physiological role for this hormone in linear bone growth.

Insulin-like growth factor-I signaling is modified during chondrocyte differentiation.

Insulin-like growth factor-I (IGF-I) is a critical regulator of skeletal growth. While IGF-I has been shown to be a potent chondrocyte mitogen in vitro, its role in chondrocyte differentiation is less well characterized. We chose to study the action of IGF-I on an accepted model of chondrocyte differentiation, the ATDC5 cell line. Insulin concentrations sufficiently high to interact with the IGF-I receptor are routinely used to induce ATDC5 cells to differentiate. Therefore, we first examined the ability of IGF-I to promote chondrocyte differentiation at physiological concentrations. IGF-I could induce differentiation of these cells at concentrations below 10 nM. However, increasing IGF-I concentrations were less potent at inducing differentiation. We hypothesized that mitogenic effects of IGF-I might inhibit its differentiating effects. Indeed, the extracellular-signal-regulated kinase (ERK)-pathway inhibitor PD98059 inhibited ATDC5 cell DNA synthesis while enhancing differentiation. This suggested that the ability of IGF-I to promote both proliferation and differentiation might require that its signaling be modulated through the differentiation process. We therefore compared IGF-I-mediated ERK activation in proliferating and hypertrophic chondrocytes. IGF-I potently induced ERK activation in proliferating cells, but minimal ERK response was seen in hypertrophic cells. In contrast, IGF-I-mediated Akt activation was unchanged by differentiation, indicating intact upstream IGF-I receptor signaling. Similar findings were observed in the RCJ3.1C5.18 chondrogenic cell line and in primary chick chondrocytes. We conclude that IGF-I promotes both proliferation and differentiation of chondrocytes and that the differentiation effects of IGF-I may require uncoupling of signaling to the ERK pathway.

Antenatal dexamethasone: effect on ovine placental 11beta-hydroxysteroid dehydrogenase type 2 expression and fetal growth.

Antenatal glucocorticoids are routinely given to women at risk for preterm delivery. The fetus is protected from excessive glucocorticoids by the placental enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD-2), which catalyzes the conversion of cortisol to its biologically inactive metabolite, cortisone. We examined the effects of antenatal dexamethasone on the expression of placental 11beta-HSD-2 in fetal sheep. Ewes were randomized to receive repeated or single courses of dexamethasone or placebo beginning at 76-78 or 104-106 d of gestation, respectively. In the single course group, the ewes received dexamethasone (6 mg, n = 7) or placebo (n = 6) as four intramuscular injections over 48 h up to 18 h before placental harvest. In the repeated course group, the ewes received the same treatment (dexamethasone, n = 10, or placebo, n = 9) once a week for 5 consecutive weeks starting at 76-78 d of gestation. Placental harvest occurred at 106-108 d of gestation in the four groups. By semi-quantitative RT-PCR, we found that placental 11beta-HSD-2 expression was lower in the fetuses of ewes exposed to a single course of dexamethasone than placebo (p < 0.05). Placental 11beta-HSD-2 expression did not differ significantly between fetuses of ewes treated with repeated courses of dexamethasone compared with placebo, or a single course of dexamethasone. Fetuses of dexamethasone treated ewes weighed less than those of placebo treated ewes (ANOVA, main effects for dexamethasone versus placebo treatment: F = 14.5, p = 0.007). Fetuses of ewes exposed to repeated courses of dexamethasone weighed less than those of ewes exposed to placebo or a single course of dexamethasone (p < 0.05). We conclude that maternal antenatal dexamethasone treatment reduces placental 11beta-HSD-2 expression and fetal weight at mid-gestation in the ovine pregnancy.