The underlying molecular mechanisms and biomarkers between periodontitis and COVID-19.

OBJECTIVE: Emerging evidence shows the clinical consequences of patient with COVID-19 and periodontitis are not promising, and periodontitis is a risk factor. Periodontitis and COVID-19 probably have a relationship. Hence, this study aimed to identify the common molecular mechanism that may help to devise potential therapeutic strategies in the future. MATERIAL AND METHODS: We analyzed two RNA-seq datasets for differential expressed genes, enrichment of biological processes, transcription factors (TFs) and deconvolution-based immune cell types in periodontitis, COVID-19 and healthy controls. Relationships between TFs and mRNA were established by Pearson correlation analysis, and the common TFs-mRNA regulatory network and nine co-upregulated TFs of the two diseases was obtained. The RT-PCR detected the TFs. RESULTS: A total of 1616 and 10201 differentially expressed gene (DEGs) from periodontitis and COVID-19 are found. Moreover, nine shared TFs and common biological processes associated with lymphocyte activation involved in immune response were identified across periodontitis and COVID-19. The cell type enrichment revealed elevated plasma cells among two diseases. The RT-PCR further confirmed the nine TFs up-regulation in periodontitis. CONCLUSION: The pathogenesis of periodontitis and COVID-19 is closely related to the expression of TFs and lymphocyte activation, which can provide potential targets for treatment.

A highly efficient nanoscale tapioca starch prepared by high-speed jet for Cu2+ removal in simulated industrial effluent.

BACKGROUND: Nanoscale tapioca starch (NTS) was successfully developed by high-speed jet in our previous study. In this study, the adsorption capacity of Cu2+ onto NTS was further discussed. The optimal adsorption conditions (pH, contact time, contact temperature, initial Cu2+ concentration, and adsorbent concentration), adsorption kinetics, isotherms, and thermodynamic were also evaluated. RESULTS: The results showed that NTS exhibited excellent performance in adsorption of Cu2+ , with adsorption capacities of 122.31 mg g-1 for Cu2+ (pH 7, 0.04 g L-1 , 0.2 g L-1 , 313.15 K and 10 min). The pseudo-second-order and Langmuir isotherms models could be used to explain the adsorption kinetics and adsorption equilibrium, respectively. The thermodynamic results showed that the adsorption process was spontaneous and endothermic with an increase in entropy. Cu2+ was adsorbed onto NTS, which was confirmed by energy dispersive spectrometry analysis. CONCLUSION: These findings indicated that NTS might be an effective, environment-friendly and renewable bio-resource adsorbent for removing heavy metals in industrial effluent. © 2021 Society of Chemical Industry.

Study on osteogenesis of zinc-loaded carbon nanotubes/chitosan composite biomaterials in rat skull defects.

Chitosan with hydroxyapatite composition, a natural polymer, may be a biomaterial of importance for bone regeneration. Carbon nanotube, a nanoscale material, has been another focus for bone restoration. Zinc, an essential trace element, contributes to the development and growth of skeletal system. The purpose of the current research was to investigate the effects of Zinc-loaded Carbon Nanotubes/Chitosan composite biomaterials in the restoration of rat skull defects, and to verify the hypothesis that these zinc ions of appropriate concentration would strengthen the osteogenesis of rat defects. Four different groups of composite biomaterials were fabricated from no Zinc Carbon nanotubes/Chitosan (GN), 0.2% Zinc-Carbon nanotubes/Chitosan (GL), 1% Zinc-Carbon nanotubes/Chitosan (GM) and 2% Zinc-Carbon nanotubes/Chitosan (GH). After characterizations, these composite biomaterials were then transplanted into rat skull defects. The experimental animals were executed at 12 weeks after transplanted surgeries, and the rat skull defects were removed for related analyses. The results of characterizations suggested the Zinc-loaded composite biomaterials possessed good mechanical and osteoinductive properties. An important finding was that the optimal osteogenic effect appeared in rat skull defects transplanted with 1% Zinc-Carbon nanotubes/Chitosan. Overall, these composite biomaterials revealed satisfactory osteogenesis, nevertheless, there was a requirement to further perfect the zinc ion concentrations to achieve the better bone regeneration.

Diverse effects of platelet-derived growth factor-BB on cell signaling pathways.

Platelet-derived growth factor-BB (PDGF-BB) is involved in the tissue repair and tumor progression effects, and act as a rapid and early effector cytokines which are released in response to pathogen-induced changes in the microenvironment. Recent researches have implicated PDGF-BB as a potential contributing factor to the spectrum of the cell signaling pathway of interrelated diseases, particularly mesangial cells, mesenchymal stem cells, human dermal fibroblasts, tumor pericytes and smooth muscle cells. In this review, we generalize the present literatures on the roles of PDGF-BB in the various interrelated diseases, providing insights or strategies into the underlying cellular and signaling mechanisms that will help guide future studies further into promising interventional targets with therapeutic potential.

Cerium oxide immobilized reduced graphene oxide hybrids with excellent microwave absorbing performance.

Microwave absorbing materials with high absorption over a broad bandwidth when they have a small thickness are strongly desired due to their widespread applications. Herein, cerium oxide immobilized reduced graphene oxide (CeO2-rGO) hybrids with excellent microwave absorbing performance have been fabricated by a versatile one-step hydrothermal approach. Modern measurement techniques, including X-ray diffraction, Raman spectroscopy, electronic microscopy, X-ray photoelectron spectroscopy and vector network analysis, have been conducted to characterize the chemical composition, microstructure and electromagnetic performance of the as-obtained hybrids. Morphological analysis reveals that the CeO2 nanocrystals are homogeneously immobilized onto the rGO surface without any significant agglomeration. Interestingly, significant enhancement in the microwave absorbing performance has been observed for all the CeO2-rGO hybrids. For example, a CeO2-rGO hybrid with a 10 : 1 mass ratio of CeO2 to GO exhibits a minimum reflection loss (RL) of -45.94 dB, which is 73.35 times and 6.14 times that of the lone CeO2 and rGO, respectively. Moreover, the CeO2-rGO hybrid shows a broadband absorption feature with an effective absorption bandwidth (RL < -10 dB) of 4.5 GHz, and can be exploited for practical application in a frequency range of 3.68-18.00 GHz via tuning of the thickness. Investigation of the structure-property correlation indicates that such enhancements are attributed to conductive loss, polarization loss and multiple reflections which are mainly derived from the unique CeO2-rGO based architecture. In addition, the higher oxygen vacancy concentration of CeO2 in hybrids can promote electron transfer between CeO2 and rGO, leading to microwave attenuation enhancement. It is expected that these CeO2-rGO hybrids can be used as new microwave absorbers.

Host genetics and viral load in primary HIV-1 infection: clear evidence for gene by sex interactions.

Research in the past two decades has generated unequivocal evidence that host genetic variations substantially account for the heterogeneous outcomes following human immunodeficiency virus type 1 (HIV-1) infection. In particular, genes encoding human leukocyte antigens (HLA) have various alleles, haplotypes, or specific motifs that can dictate the set-point (a relatively steady state) of plasma viral load (VL), although rapid viral evolution driven by innate and acquired immune responses can obscure the long-term relationships between HLA genotypes and HIV-1-related outcomes. In our analyses of VL data from 521 recent HIV-1 seroconverters enrolled from eastern and southern Africa, HLA-A*03:01 was strongly and persistently associated with low VL in women (frequency = 11.3 %, P < 0.0001) but not in men (frequency = 7.7 %, P = 0.66). This novel sex by HLA interaction (P = 0.003, q = 0.090) did not extend to other frequent HLA class I alleles (n = 34), although HLA-C*18:01 also showed a weak association with low VL in women only (frequency = 9.3 %, P = 0.042, q > 0.50). In a reduced multivariable model, age, sex, geography (clinical sites), previously identified HLA factors (HLA-B*18, B*45, B*53, and B*57), and the interaction term for female sex and HLA-A*03:01 collectively explained 17.0 % of the overall variance in geometric mean VL over a 3-year follow-up period (P < 0.0001). Multiple sensitivity analyses of longitudinal and cross-sectional VL data yielded consistent results. These findings can serve as a proof of principle that the gap of "missing heritability" in quantitative genetics can be partially bridged by a systematic evaluation of sex-specific associations.

Cumulative impact of host and viral factors on HIV-1 viral-load control during early infection.

In HIV-1 infection, the early set-point viral load strongly predicts both viral transmission and disease progression. The factors responsible for the wide spectrum of set-point viral loads are complex and likely reflect an interplay between the transmitted virus and genetically defined factors in both the transmitting source partner and the seroconverter. Indeed, analysis of 195 transmission pairs from Lusaka, Zambia, revealed that the viral loads in transmitting source partners contributed only ∼2% of the variance in early set-point viral loads of seroconverters (P = 0.046 by univariable analysis). In multivariable models, early set-point viral loads in seroconverting partners were a complex function of (i) the viral load in the source partner, (ii) the gender of the seroconverter, (iii) specific HLA class I alleles in the newly infected partner, and (iv) sharing of HLA-I alleles between partners in a transmission pair. Each of these factors significantly and independently contributed to the set-point viral load in the newly infected partner, accounting for up to 37% of the variance observed and suggesting that many factors operate in concert to define the early virological phenotype in HIV-1 infection.

HLA-B*57 versus HLA-B*81 in HIV-1 infection: slow and steady wins the race?

Two human leukocyte antigen (HLA) variants, HLA-B*57 and -B*81, are consistently known as favorable host factors in human immunodeficiency virus type 1 (HIV-1)-infected Africans and African-Americans. In our analyses of prospective data from 538 recent HIV-1 seroconverters and cross-sectional data from 292 subjects with unknown duration of infection, HLA-B*57 (mostly B*57:03) and -B*81 (exclusively B*81:01) had mostly discordant associations with virologic and immunologic manifestations before antiretroviral therapy. Specifically, relatively low viral load (VL) in HLA-B*57-positive subjects (P ≤ 0.03 in various models) did not translate to early advantage in CD4(+) T-cell (CD4) counts (P ≥ 0.37). In contrast, individuals with HLA-B*81 showed little deviation from the normal set point VL (P > 0.18) while maintaining high CD4 count during early and chronic infection (P = 0.01). These observations suggest that discordance between VL and CD4 count can occur in the presence of certain HLA alleles and that effective control of HIV-1 viremia is not always a prerequisite for favorable prognosis (delayed immunodeficiency). Of note, steady CD4 count associated with HLA-B*81 in HIV-1-infected Africans may depend on the country of origin, as observations differed slightly between subgroups enrolled in southern Africa (Zambia) and eastern Africa (Kenya, Rwanda, and Uganda).

No genetic causal association between periodontitis and ankylosing spondylitis: a bidirectional two-sample mendelian randomization analysis.

BACKGROUND: Observational studies that reveal an association between periodontitis (PD) and ankylosing spondylitis (AS) exist. However, observational research is prone to reverse causality and confounding factors, which make it challenging to infer cause-and-effect relationships. We conducted a two-sample Mendelian randomization (MR) study to examine the causal relationship between the genetic prediction of PD and AS. METHODS: In our study, single-nucleotide polymorphisms (SNPs) were defined as instrumental variables (IVs). The genetic association with PD came from the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) consortium, wherein 17353 cases of European ancestry and 28210 controls of European ancestry were included in this study. The genetic association with AS from the Neale Laboratory Consortium included 337,159 individuals from the United Kingdom, with 968 cases and 336,191 controls. MR analysis was mainly performed using the inverse-variance weighted (IVW) method. In addition, the robustness of the study findings was assessed using sensitivity, pleiotropy, and heterogeneity analyses. RESULTS: Eighteen independent SNPs with P-values significantly smaller than 1 × 10- 5 were used as IV SNPs for PD, while 39 independent SNPs with P-values significantly smaller than 1 × 10- 5 were used as IV SNPs for AS. The results of the IVW method revealed no causal association between PD and AS (odds ratio = 1.00, 95% confidence interval: 0.99953 to 1.00067, P = 0.72). The MR-Egger method did not support the causal association between PD and AS. It is unlikely that horizontal pleiotropy distorts causal estimates based on sensitivity analysis. No significant heterogeneity was observed in the Q test. The ''leave-one-out'' analysis demonstrated that the robustness of our results was unaffected by eliminating any of the IVs. Likewise, no significant causative effect for AS on PD was observed in the inverse MR analysis. CONCLUSIONS: The study results do not support shared heritability or a causal association between PD and AS.

HLA-B signal peptide polymorphism influences the rate of HIV-1 acquisition but not viral load.

Human leukocyte antigen alleles influence the immune response to HIV-1. Signal peptides cleaved from those alleles bind to HLA-E and mediate natural killer cell function. Signal peptides of HLA-A and HLA-C proteins carry methionine (Met) at anchor position 2 (P2); those of HLA-B carry Met or threonine (Thr). Different P2 residues alter HLA-E binding to its cognate receptors and may impact HIV-1 acquisition. Among Zambian couples (N = 566) serodiscordant for HIV-1, P2-Met accelerated acquisition in the HIV-1-negative partner (relative hazard [RH], 1.79). Among seroconverting Zambian (n = 240) and Rwandan (n = 64) partners, P2-Met also accelerated acquisition (RH, 1.47 and RH, 1.83 respectively). HLA-B alleles displaying the reportedly protective Bw4 epitope carry P2-Thr. Bw4/P2-Thr and Bw6/P2-Thr showed similar protective effects compared with Bw6/P2-Met. Neither motif was associated with viral load. The influence of HLA-B alleles on HIV/AIDS may derive from multiple motifs in and beyond the mature proteins.

Correlation between differences in intraoperative jumping gaps and soft tissue changes around immediate implant placement and provisionalization in the maxillary anterior region.

OBJECTIVES: This study aims to evaluate the correlation between differences in intraoperative jumping gaps and soft tissue changes around immediate implant placement and provisionalization (IIPP) in the maxillary anterior region. Results will provide a basis for clinical evaluation of the change trend and long-term stability of the labial soft tissue contours of patients with different jumping gaps. METHODS: Thirty-two patients with single tooth loss in the maxillary aesthetic area were enrolled, and they all received immediate implant placement and restoration. All patients were divided into three groups: A, B, and C according to the size of the jumping gap, group A: horizontal defect dimension (HDD) ≤2 mm; group B: 2 mm3 mm. Geomagic studio 2013 was used to quantitatively analyze the contour volume of the soft tissue around the implant and the level of the labial gingival margin. The pink esthetic score (PSE) was used for the final aesthetic evaluation. RESULTS: All implants had osseointegration within 6 months after the surgery. The average thickness of soft tissue contour volume changed by 0.62 mm±0.15 mm, and the average PES was 11.09±0.99. The changes in the gingival mucosa levels in the three groups at 6 months after operation were 0.45 mm±0.11 mm, 0.40 mm±0.12 mm, and 0.35 mm± 0.11 mm, respectively. The changes in the average thickness of the soft tissue contour volume in the three groups at 6 months after the operation were 0.77 mm±0.16 mm, 0.63 mm±0.17 mm, and 0.54 mm±0.11 mm. A moderate negative correlation was found between the jumping gap size and the gingival mucosa level, and the average thickness changed. No significant correlation was found between size of jumping gap and PES. CONCLUSIONS: Although the contour volume of the labial soft tissue continuously decreased within 6 months after IIPP in the maxillary anterior region, the surgical procedure can achieve a satisfactory aesthetic effect, and the level of soft tissue around the implant can be well maintained.

Immediate Implant Placement With or Without Immediate Provisionalization in the Maxillary Esthetic Zone: A Systematic Review and Meta-analysis.

PURPOSE: To determine whether immediate implant placement and loading renders different outcomes from delayed loading with respect to midfacial mucosal level in the maxillary esthetic area. MATERIALS AND METHODS: A literature search was conducted in four electronic databases (PubMed, Web of Science, Embase, and Cochrane), identifying eligible clinical studies published prior to December 2021. Only randomized controlled trials (RCTs) comparing immediate implant placement with or without immediate loading in the maxillary esthetic zone with a mean follow-up of at least 12 months were selected for qualitative analysis and meta-analysis. The Cochrane Risk of Bias tool was adopted to assess the quality of the evidence. The heterogeneity between the pooled literature was analyzed through the chi-square test (P < .05) and quantified by the I2 index. A mixed-effects model was applied if it appeared that there was noteworthy heterogeneity; otherwise, a random-effects model was chosen. For continuous outcomes, the estimate of relative effect was presented to display the standardized mean differences (SMDs) and 95% CIs. For dichotomous variables, the Mantel-Haenszel statistical method was applied with effect sizes expressed as risk ratios (RRs) and 95% CIs. This study is registered on PROSPERO with number CRD42017078611. RESULTS: Out of 5,553 records, 8 RCTs were involved, providing data for 324 immediately placed implants (immediate implants subjected to immediate loading [IPIL]: 163; immediate implants subjected to delayed loading [IPDL]: 161) that had been in function within 12 to 60 months. Meta-analyses revealed significantly lower midfacial mucosal level changes for IPIL compared with IPDL, pointing to 0.48 mm (95% CI: -0.84 to -0.12; P = .01), as well as more significant papillary recession after IPDL (SMD -0.16; 95% CI: -0.31 to 0.00; P = .04). The differences regarding implant survival and marginal bone loss between the two loading groups showed no statistical significance. The result of metaanalyses revealed similar plaque score (SMD 0.03; 95% CI: -0.22 to 0.29; P = .79) and probing depth (SMD -0.09; 95% CI: -0.23 to 0.05; P = .21) for IPIL and IPDL. On the other hand, IPIL induced a trend toward more bleeding on probing (SMD 0.22; 95% CI: 0.01 to 0.42; P = .04) and less change in facial ridge dimension (SMD 0.94; 95% CI: -1.49 to -0.39; P < .01). CONCLUSION: After a follow-up ranging from 12 to 60 months, midfacial mucosa level change was 0.48 mm lower following IPIL compared with IPDL. Immediate implant placement and loading is conducive to the preservation of physiologic soft and hard tissue architecture, appearing to offer considerable benefits in the anterior zone. In summary, IPIL should be considered in the esthetic zone if the primary implant stability permits. Int J Oral Maxillofac Implants 2023;38:422-434. doi: 10.11607/jomi.10112.

[Retracted] EVI­1 acts as an oncogene and positively regulates calreticulin in breast cancer.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that, for the Transwell cell migration and invasion assay experiments shown in Fig. 3 on p. 1650, there were several panels showing overlapping sections of data; moreover, certain of the data shown in this Figure were also strikingly similar to data appearing in different form in Fig. 4 in another article written by different authors at a different research institute [Liu J and Duan X: PA­MSHA induces apoptosis and suppresses metastasis by tumor associated macrophages in bladder cancer cells. Cancer Cell Int 17: 76, 2017].  Owing to the fact that the contentious data in the above article had already been published prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 19: 1645­1653, 2019; DOI: 10.3892/mmr.2018.9796].

The relationship between labial soft tissue changes and jumping spaces after immediate implant placement and restoration in the anterior maxilla: A prospective study.

Oral implants have been increasingly used in the treatment of edentulous patients or those with dentition defects due to reliable treatment procedure and favorable long-term prognosis. We investigated the changes of labial soft tissue contours with different jumping spaces after immediate implant placement and restoration (IIPR) in the maxillary esthetic area and also provided a long-term stability measurement for the changing trend of soft tissue contour. All patients had been separated into three groups based on the jumping space: group A (horizontal defect dimension [HDD] 2 mm), group B (2 mm < HDD 3 mm), and group C (HDD > 3 mm) and the digital impressions were obtained in the first, third, and sixth month after the operation. The changes of gingival mucosa levels, the average thickness of soft tissue contour volume, and the linear change of submarginal level decreased gradually across the three groups, with the largest change of submarginal level being at 5mm. The size of the jumping space was moderately negatively correlated with the level and average thickness of gingival mucosa and the linear changes of 3 mm and 5 mm under gingival margin, while there was no significant correlation with pink esthetic score (PES) and the linear change of the 1 mm under the gingival margin. Generally, IIPR of upper anterior teeth can achieve esthetic satisfaction, and the level of soft tissue around the implant can be well preserved.

Deciphering genetic causality between inflammatory bowel disease and periodontitis through bi-directional two-sample Mendelian randomization.

Inflammatory bowel disease (IBD) and periodontitis are reported to be closely associated; however, whether there is a causal association between them remains unclear. To explore the existence of this causality, this study applied a bidirectional two-sample Mendelian randomization (MR). The genetic variants were obtained from the summary statistics of genome-wide association studies of IBD, including its subtypes CD and UC, and periodontitis. 175, 148, 113, and six single-nucleotide polymorphisms were selected as instrumental variables for IBD, CD, UC, and periodontitis, respectively. In MR analysis, random-effects inverse-variance weighted was used as the primary method, and weighted median and MR Egger regression were applied as the complementary method. A series of sensitivity analyses were also conducted to ensure the reliability of the results. None of these analyses found a significant effect of genetically proxied IBD and its subtypes on periodontitis, and vice versa. Subsequent sensitivity analyses did not detect any horizontal pleiotropy and heterogeneity. Caution should be exerted when it comes to clinical relevance and further studies are needed to clarify the relationship between IBD and periodontitis.

Women's Psychological Health, Family Function, and Social Support During Their Third Trimester of Pregnancy Within the COVID-19 Epidemic: A Cross-sectional Survey.

OBJECTIVE: This study aims to investigate women's psychological health, family function, and social support during the third trimester within the coronavirus disease 2019 (COVID-19) epidemic. METHOD: From January 30, 2020, to February 26, 2020, a total of 177 pregnant women during their third trimester (mean gestation time was 37.05 ± 4.06 wk) in a maternal and children's hospital were investigated using the Self-Rating Anxiety Scale (SAS), the Edinburgh Postnatal Depression Scale, the Family APGAR Index, and the Perceived Social Support Scale. Nonparametric tests were conducted in the study. The statistical significance was set as P < 0.05. RESULT: The incidence rate of the participants' anxiety and depression during the COVID-19 epidemic was 19.21% and 24.29%, respectively. The participants' greatest concerns in the previous week were the risk of virus transmission (79.66%), and the prenatal examination and fetal growth (70.62%). The SAS ranks were higher in the participants who were concerned about the prenatal examination and fetal growth and work-related affairs. CONCLUSION: The participants' psychological health was indirectly affected by the epidemic through the supply of medical resources and work-related factors. The medical staff should employ family support and social resources to guarantee the accessibility of medical services and living materials to decrease the pregnant women's stress and further improve their psychological health.

Psychological effects of the COVID-19 outbreak on nurses working in tertiary women's and children's hospitals from Sichuan, China: A cross-sectional study.

The evolving COVID-19 pandemic is placing unprecedented pressures on health systems. Accumulative studies suggest that nurses were more likely to develop negative psychiatric outcomes following a public health disaster than other medical staffs, due to their more frequent and closer contact with patients. We examined the psychological status of nurses working in the tertiary women's and children's hospitals in Sichuan, China, in order to explore the possible effect of the COVID-19. The cross-sectional survey was conducted at the peak period of COVID-19 among 1971 nurses. Their anxiety, depression and self-efficacy were assessed by the seven-item anxiety scale (GAD-7), the nine-item Patient Health Questionnaire (PHQ-9), and the General Self-efficacy Scale (GSES), respectively. 1934 valid questionnaires were returned with a response rate of 98.1%. We found that 29.3% and 22.7% of the nurses were identified with anxiety and depressive symptoms, respectively. The median score of GSES was 30, which was at the upper middle level among all populations. Nurses having longer working years and cold-like symptoms, those who were at work during breakout period and working in pediatric ward were significantly associated with the presence of anxiety and depression. Findings suggest that the epidemic of COVID-19 does not necessarily affect the psychological health of nurses working in women's and children's hospitals in Sichuan. The results of this study could serve as valuable suggestions to direct the promotion of psychological well-being among targeted nurses.

Extracorporeal membrane oxygenation causes loss of intestinal epithelial barrier in the newborn piglet.

Extracorporeal membrane oxygenation (ECMO) is an important life-support system used in neonates and young children with intractable cardiorespiratory failure. In this study, we used our porcine neonatal model of venoarterial ECMO to investigate whether ECMO causes gut barrier dysfunction. We subjected 3-wk-old previously healthy piglets to venoarterial ECMO for up to 8 h and evaluated gut mucosal permeability, bacterial translocation, plasma levels of bacterial products, and ultrastructural changes in gut epithelium. We also measured plasma lipopolysaccharide (LPS) levels in a small cohort of human neonates receiving ECMO. In our porcine model, ECMO caused a rapid increase in gut mucosal permeability within the first 2 h of treatment, leading to a 6- to 10-fold rise in circulating bacterial products. These changes in barrier function were associated with cytoskeletal condensation in epithelial cells, which was explained by phosphorylation of a myosin II regulatory light chain. In support of these findings, we also detected elevated plasma LPS levels in human neonates receiving ECMO, indicating a similar loss of gut barrier function in these infants. On the basis of these data, we conclude that ECMO is an independent cause of gut barrier dysfunction and bacterial translocation may be an important contributor to ECMO-related inflammation.

Repression of CFTR activity in human MMNK-1 cholangiocytes induces sulfotransferase 1E1 expression in co-cultured HepG2 hepatocytes.

Mouse models of cystic fibrosis (CF) indicate that sulfotransferase (SULT) 1E1 is significantly induced in livers of many mice lacking cystic fibrosis transmembrane receptor (CFTR) activity. Increased SULT1E1 activity results in the alteration of estrogen-regulated protein expression in the livers of these mice. In this study, human MMNK-1 cholangiocytes with repressed CFTR function were used to induce SULT1E1 expression in human HepG2 hepatocytes to investigate whether SULT1E1 can be increased in human CF liver. CFTR expression was inhibited in MMNK-1 cholangiocytes using CFTR-siRNA, then the MMNK-1 and HepG2 cells were co-cultured in a membrane-separated Transwell system. Expression of SULT1E1 and selected estrogen-regulated proteins were then assayed in the HepG2 cells. Results demonstrate that inhibition of CFTR expression in MMNK-1 cells results in the induction of SULT1E1 message and activity in HepG2 cells in the Transwell system. The expression of estrogen-regulated proteins including insulin-like growth factor (IGF)-1, glutathione-S-transferase (GST) P1 and carbonic anhydrase (CA) II expression are repressed in the HepG2 cells cultured with the CFTR-siRNA-MMNK-1 cells apparently in response to the increased sulfation of beta-estradiol. Thus, we have shown that co-culture of HepG2 hepatocytes with MMNK-1 cholangiocytes with siRNA repressed CFTR expression results in the selective induction of SULT1E1 in the HepG2 cells. Loss of CFTR function in cholangiocytes may have a paracrine regulatory effect on hepatocytes via the induction of SULT1E1 and the increased sulfation of beta-estradiol. Experiments are presently underway in our laboratory to elucidate the identity of these paracrine regulatory factors.

Increased SULT1E1 activity in HepG2 hepatocytes decreases growth hormone stimulation of STAT5b phosphorylation.

Mouse models of cystic fibrosis (CF) display increased sulfotransferase 1E1 (SULT1E1) activity in hepatocytes of cystic fibrosis transmembrane receptor (CFTR)-deficient animals. SULT1E1 is responsible for the sulfation and inactivation of beta-estradiol (E2) at physiological concentrations. IGF-1 message levels in CFTR(-/-) mouse livers were positively correlated with body weight and negatively correlated with SULT1E1 activity. Growth hormone (GH) is important in the regulation of hepatic IGF-1 expression indicating that E2 levels are involved with GH signaling in hepatocytes. To investigate the effects of E2 and SULT1E1 activity on GH signal transduction in human hepatocytes, SULT1E1 was stably expressed in HepG2 cells. Effects of increased E2 sulfation on the GH signaling pathway and E2-regulated gene expression were examined. Pretreatment of HepG2 cells with 10nM E2 prior to GH stimulation increased STAT5b phosphorylation and IGF-1 expression. In SULT1E1-transfected HepG2 cells, GH-stimulated STAT5b phosphorylation was significantly decreased. E2 treatment had no effect on STAT5b phosphorylation in the absence of GH stimulation. E2 also had no effect on Jak-2 phosphorylation. E2 has an apparent rapid action on increasing GH-stimulated STAT5b phosphorylation that was not attenuated by the estrogen receptor antagonist, ICI 182,780. Physiological levels of E2 in HepG2 cells increase GH stimulation of IGF-1 production apparently through increased phosphorylated STAT5b levels and transcriptional activation of the IGF-1 gene. The enhanced SULT1E1 activity may have a role in inhibiting GH-stimulated STAT5b phosphorylation and IGF-1 synthesis via the sulfation and inactivation of E2.