Placental inflammatory injury induced by chlorinated polyfluorinated ether sulfonate (F-53B) through NLRP3 inflammasome activation.

Chlorinated polyfluorinated ether sulfonate, commercially known as F-53B, has been associated with adverse birth outcomes. However, the reproductive toxicology of F-53B on the placenta remains poorly understood. To address this gap, we examined the impact of F-53B on placental injury and its underlying molecular mechanisms in vivo. Pregnant C57BL/6 J female mice were randomly allocated to three groups: the control group, F-53B 0.8 µg/kg/day group, and F-53B 8 µg/kg/day group. After F-53B exposure through free drinking water from gestational day (GD) 0.5-14.5, the F-53B 8 µg/kg/day group exhibited significant increases in placental weights and distinctive histopathological alterations, including inflammatory cell infiltration, heightened syncytiotrophoblast knots, and a loosened trophoblastic basement membrane. Within the F-53B 8 µg/kg/day group, placental tissue exhibited increased apoptosis, as indicated by increased caspase3 activation. Furthermore, F-53B potentially induced the NF-κB signaling pathway activation through IκB-α phosphorylation. Subsequently, this activation upregulated the expression of inflammatory cytokines and components of the NLRP3 inflammasome, including activated caspase1, IL-1ß, IL-18, and cleaved gasdermin D (GSDMD), ultimately leading to pyroptosis in the mouse placenta. Our findings reveal a pronounced inflammatory injury in the placenta due to F-53B exposure, suggesting potential reproductive toxicity at concentrations relevant to the human population. Further toxicological and epidemiological investigations are warranted to conclusively assess the reproductive health risks posed by F-53B.

[Assisted reproductive technology for male patients with end-stage renal disease: A case-based discussion on strategies and ethical issues].

OBJECTIVE: To explore normalized and reasonable strategies of assisted reproductive technology (ART) for patients with end-stage renal disease (ESRD) under ethical supervision based on the experience with a case of ART for an ESRD male. METHODS: A male patient with ESRD successfully fathered a child through in vitro intracytoplasmic sperm injection (ICSI) in our center. We performed an epidemiological analysis, reviewed the relevant literature and explored the feasibility, ethical issues and strategies of ART for male patients with ESRD. RESULTS: ESRD affected the reproductive hormone levels, sperm quality and erectile function of the patient. Considering the contradictions between the reproductive right and the uncertainty of disease prognosis of the patient and the health of the offspring and his wife, we comprehensively evaluated the physical and mental conditions of the patient, obtained the informed consent, submitted the case to the Ethics Committee of Reproductive Medicine. CONCLUSIONS: With respect to ART for ESRD patients, importance should be attached to their rights of reproduction and choice of reproductive technology. In the process of ART, the physical conditions of the patient ought to be evaluated comprehensively and rigorously, and the related ethical principles followed strictly.

Laser speckle formed disordered micro-meander structures for light extraction enhancement of flexible organic light-emitting diodes.

A new approach for efficiently recovering the wasted light energy in conventional flexible organic light-emitting diodes (FOLEDs) is developed by implementing disordered micro-meander structures (DMMs) via laser speckle holography technology. Compared to conventional flat device architecture, the structured FOLEDs with DMMs result in substantial improvement of the device efficiency and superior angular color stability. The resulting current efficiency (CE) and external quantum efficiency (EQE) are 1.31 and 1.39 times that of a common flat structure, respectively. Moreover, the proposed DMMs micro-structure simultaneously offers the unique characteristics of angular color stability with a wide viewing angle, which is usually considered as the criteria of the high-quality lighting applications. We hope that the demonstrated method could provide an alternative way for the development of high efficiency flexible OLEDs.

Early-life gut microbial colonization shapes Th1/Th2 balance in asthma model in BALB/c mice.

BACKGROUND: We aimed to investigate the effect of early-life diverse microbial exposures on gut microbial colonization in an OVA-induced asthma model in BALB/c mice. METHODS: BALB/c mice were divided into 4 groups: A, offsprings were kept in a SPF environment during fetal, lactation, and childhood periods; B, offsprings were kept in the SPF environment during fetal and lactation periods, and kept in the general environment during childhood; C, offsprings were kept in the SPF environment only during fetal period, and then kept in the general environment; and D, offsprings were kept in the general environment during whole periods. The diversity of intestinal flora was analyzed using denaturing gradient gel electrophoresis. Mice were sensitized with OVA to establish an animal model of asthma. Then asthma-related inflammatory cytokines and histological analysis were performed. RESULTS: The diversity of intestinal microflora in group D was significantly higher than groups A, B and C at three days and three weeks after birth, and the diversity of intestinal microflora in groups C and D were significantly higher than groups A and B at five weeks after birth. The pathologic scores of OVA-induced asthmatic mice in group D were significantly lower than group A, and serum IFN-γ levels and the IFN-γ/IL-4 ratio in group D were significantly higher than group A. CONCLUSIONS: Exposure to diverse microbial environments in early life affects gut microbial colonization in BALB/c mice. The diversity of the intestinal flora in early life may prevent airway inflammation in asthma via regulating the Th1/Th2 balance.

[Application of calcium ionophore A23187 in ICSI for globozoospermia: A report of 2 cases and review of the literature].

OBJECTIVE: To investigate the pathogenesis of globozoospermia, fertilization ability of round-headed sperm, and the application value of assisted oocyte activation in intracytoplasmic sperm injection (ICSI) for the wives of glohozoospermia men. METHODS: We collected oocytes from the wives of 2 globozoospermia patients and randomly divided them into two groups after ICSI to receive calcium ionophore A23187-activation and conventional treatment, respectively. We reviewed the relevant literature published at home and abroad, and discussed the etiology of globozoospermia, fertilization ability of round-headed sperm, and treatment options for this disease. RESULTS: Quality embryos were obtained in the A23187-activation group while no fertilized oocytes, oocyte cleavage, quality embryos, or blastular formation were found in the conventional treatment group. Both women achieved pregnancy and gave birth to healthy neonates after transfer of the quality embryos from the A23187-activation group. CONCLUSION: Calcium ionophore A23187 can be applied to ICSI for the wives of globozoospermia men and bring about desirable clinical outcomes. Meanwhile, attention should be paid to its safety.

A novel high nitrogen nickel-free coronary stents system: evaluation in a porcine model.

OBJECTIVE: To study the safety of the novel high nitrogen nickel-free austenitic stainless steel bare metal stents (BMS) in a recognized porcine coronary model and to select a better grid structure of it. METHODS: Three types of stents were randomly implanted in different coronary arteries of the same pig: 316 L stainless steel BMS (316 L-BMS) (n=12), novel high nitrogen nickel-free stents Grid A (NF-A-BMS) (n=12) and novel high nitrogen nickel-free stents Grid B (NF-B-BMS) (n=12). In total, eighteen animals underwent successful random placement of 36 oversized stents in the coronary arteries. Coronary angiography was performed after 36 d of stents implantation. Nine animals were respectively sacrificed after 14 d and 36 d for histomorphologic analysis. RESULTS: Quantitative coronary angiography (QCA) showed similar luminal loss (LL) in the three groups: (0.21 ± 0.17) mm for 316 L-BMS, (0.16 ± 0.12) mm for NF-A-BMS, (0.24 ± 0.15) mm for NF-B-BMS (P>0.05). Histomorphomeric analysis after 15 d and 36 d revealed that there was also no significant difference among the three groups in neointimal area (NA) with similar injury scores respectively. High magnification histomorphologic examination showed similar inflammation scores in the three groups, but NF-A-BMS group had poorer endothelialization scores compared with NF-B-BMS group, 2.00 ± 0.63 vs. 2.83 ± 0.41 (P=0.015) at 15 d, which also could be proved by the scanning electron microscope. However, the difference could not been observed at 36 d. CONCLUSION: The novel NF-BMS showed similar safety as 316 L-BMS during the short-term study. NF-B-BMS had better endothelialization than NF-A-BMS and this may owe to the specific strut units.

[Progress in the effects of injury and regeneration of gustatory nerves on the taste functions in animals].

The sensor of the taste is the taste bud. The signals originated from the taste buds are transmitted to the central nervous system through the gustatory taste nerves. The chorda tympani nerve (innervating the taste buds of the anterior tongue) and glossopharyngeal nerve (innervating the taste buds of the posterior tongue) are the two primary gustatory nerves. The injuries of gustatory nerves cause their innervating taste buds atrophy, degenerate and disappear. The related taste function is also impaired. The impaired taste function can be restored after the gustatory nerves regeneration. The rat model of cross-regeneration of gustatory nerves is an important platform for research in the plasticity of the central nervous system. The animal behavioral responses and the electrophysiological properties of the gustatory nerves have changed a lot after the cross-regeneration of the gustatory nerves. The effects of the injury, regeneration and cross-regeneration of the gustatory nerves on the taste function in the animals will be discussed in this review. The prospective studies on the animal model of cross-regeneration of gustatory nerves are also discussed in this review. The study on the injury, regeneration and cross-regeneration of the gustatory nerves not only benefits the understanding of mechanism for neural plasticity in gustatory nervous system, but also will provide theoretical basis and new ideas for seeking methods and techniques to cure dysgeusia.

Comparison of stigmatizing views towards COVID-19 and mental disorders among adolescent and young adult students in China.

Objective: Infectious diseases including COVID-19 and mental disorders are two of the most common health conditions associated with stigma. However, the comparative stigma of these two conditions has received less attention in research. This study aimed to compare the prevalence of stigmatizing views toward people with COVID-19 and mental disorders and the factors associated with these views, among a large sample of adolescent and young adult students in China. Methods: A total of 9,749 adolescents and young adults aged 15-24 years completed a survey on stigmatizing attitudes toward COVID-19 and mental disorders, as well as mental health-related factors, including general mental health status and symptoms of depression, anxiety, insomnia, and post-traumatic stress disorder (PTSD). Multivariable linear regression analyses were conducted to identify factors associated with stigmatizing views. Findings: The prevalence of COVID-19 and mental disorders-related stigma was 17.2% and 40.7%, respectively. COVID-19-related stigma scores were significantly higher among male students (ß = 0.025, p < 0.05), those without quarantine experience (ß = 0.035, p < 0.001), those with lower educational level (p < 0.001), those with lower family income (p < 0.01), and those with higher PTSD symptoms (ß = 0.045, p < 0.05). Mental disorder-related stigma scores were significantly higher among individuals with average and lower-than-average levels of family income (p < 0.01), depression symptoms (ß = 0.056, p < 0.001), anxiety symptoms (ß = 0.051, p < 0.001), and mental health problems (ß = 0.027, p < 0.05). Conclusion: The stigma of mental disorders is higher in the youth population than the stigma of COVID-19. Factors associated with stigmatizing attitudes toward people with COVID-19 and mental disorders varied across the youth. Stigma-reduction interventions among the youth should be targeted specifically to COVID-19 or mental disorders conditions.

Environmental pollutant pre- and polyfluoroalkyl substances are associated with electrocardiogram parameters disorder in adults.

Environmental pollutants exposure might disrupt cardiac function, but evidence about the associations of per- and polyfluoroalkyl substances (PFASs) exposure and cardiac conduction system remains sparse. To explore the associations between serum PFASs exposure and electrocardiogram (ECG) parameters changes in adults, we recruited 1229 participants (mean age: 55.1 years) from communities of Guangzhou, China. 13 serum PFASs with detection rate > 85% were analyzed finally. We selected 6 ECG parameters [heart rate (HR), PR interval, QRS duration, Bazett heart rate-corrected QT interval (QTc), QRS electric axis and RV5 + SV1 voltage] as outcomes. Generalized linear models (GLMs) and Bayesian kernel machine regression (BKMR) model were conducted to explore the associations of individual and joint PFASs exposure and ECG parameters changes, respectively. We detected significant associations of PFASs exposure with decreased HR, QRS duration, but with increased PR interval. For example, at the 95th percentile of 6:2 Cl-PFESA, HR and QRS duration were - 6.98 [95% confidence interval (CI): - 9.07, - 4.90] and - 6.54(95% CI: -9.05, -4.03) lower, but PR interval was 7.35 (95% CI: 3.52, 11.17) longer than those at the 25th percentile. Similarly, significant joint associations were observed in HR, PR interval and QRS duration when analyzed by BKMR model.

Maternal transfer of F-53B inhibited neurobehavior in zebrafish offspring larvae and potential mechanisms: Dopaminergic dysfunction, eye development defects and disrupted calcium homeostasis.

Maternal exposure to environment toxicants is an important risk factor for neurobehavioral health in their offspring. In our study, we investigated the impact of maternal exposure to chlorinated polyfluoroalkyl ether sulfonic acids (Cl-PFESAs, commercial name: F-53B) on behavioral changes and the potential mechanism in the offspring larvae of zebrafish. Adult zebrafish exposed to Cl-PFESAs (0, 0.2, 2, 20 and 200 µg/L) for 21 days were subsequently mated their embryos were cultured for 5 days. Higher concentrations of Cl-PFESAs in zebrafish embryos were observed, along with, reduced swimming speed and distance travelled in the offspring larvae. Molecular docking analysis revealed that Cl-PFESAs can form hydrogen bonds with brain-derived neurotropic factor (BDNF), protein kinase C, alpha, (PKCα), Ca2+-ATPase and Na, K - ATPase. Molecular and biochemical studies evidenced Cl-PFESAs induce dopaminergic dysfunction, eye developmental defects and disrupted Ca2+ homeostasis. Together, our results showed that maternal exposure to Cl-PFESAs lead to behavioral alteration in offspring mediated by disruption in Ca2+ homeostasis, dopaminergic dysfunction and eye developmental defects.

Prognostic differences of catestatin among young and elderly patients with acute myocardial infarction.

BACKGROUND: Previous studies have reported inconsistent findings regarding the association between catestatin and outcomes of acute myocardial infarction (AMI). This study aims to investigate the prognostic value of catestatin for long-term outcomes in patients with AMI. METHODS: One hundred and sixty-five patients with AMI were enrolled in this series. The plasma catestatin levels at baseline and clinical data were collected. All patients were followed up for four years to investigate whether there were major adverse cardiovascular events (MACEs), including cardiovascular death, recurrent AMI, rehospitalization for heart failure, and revascularization. RESULTS: There were 24 patients who had MACEs during the follow-up period. The MACEs group had significantly lower plasma catestatin levels (0.74±0.49 ng/mL vs. 1.10±0.79 ng/mL, P=0.033) and were older (59.0±11.4 years old vs. 53.2±12.8 years old, P=0.036). The rate of MACEs was significantly higher in the elderly group (≥60 years old) than in the young group (<60 years old) (23.8% [15/63] vs. 8.8% [9/102], P=0.008). The catestatin level was significantly lower in the MACEs group than that in the non-MACEs group (0.76±0.50 ng/mL vs. 1.31±0.77 ng/mL, P=0.012), and catestatin was significantly associated with MACEs (Kaplan Meier, P=0.007) among the elderly group, but not in the young group (Kaplan Meier, P=0.893). In the Cox proportional hazards regression, high catestatin was one of the independent factors for predicting MACEs after adjustment for other risk factors (hazard ratio 0.19, 95% confidence interval 0.06-0.62, P=0.006) among elderly patients. CONCLUSIONS: Elderly AMI patients with lower plasma catestatin levels are more likely to develop MACEs. Catestatin may be a novel marker for the long-term prognosis of AMI, especially in elderly patients.

Environmentally relevant concentrations of F-53B induce eye development disorders-mediated locomotor behavior in zebrafish larvae.

The perfluorooctane sulfonate alternative, F-53B, induces multiple physiological defects but whether it can disrupt eye development is unknown. We exposed zebrafish to F-53B at four different concentrations (0, 0.15, 1.5, and 15 µg/L) for 120 h post-fertilization (hpf). Locomotor behavior, neurotransmitters content, histopathological alterations, morphological changes, cell apoptosis, and retinoic acid signaling were studied. Histology and morphological analyses showed that F-53B induced pathological changes in lens and retina of larvae and eye size were significantly reduced as compared to control. Acridine orange (AO) staining revealed a dose-dependent increase in early apoptosis, accompanied by upregulation of p53, casp-9 and casp-3 genes. Genes related to retinoic acid signaling (aldh1a2), lens developmental (cryaa, crybb, crygn, and mipa) and retinal development (pax6, rx1, gant1, rho, opn1sw and opn1lw) were significantly downregulated. In addition, behavioral responses (swimming speed) were significantly increased, while no significant changes in the neurotransmitters (dopamine and acetylcholine) level were observed. Therefore, in this study we observed that exposure to F-53B inflicted histological and morphological changes in zebrafish larvae eye, induced visual motor dysfunctions, perturbed retinoid signaling and retinal development and ultimately triggering apoptosis.

[Soil organic and inorganic carbon pools as affected by straw return modes under a wheat-maize rotation system in the Guanzhong Plain, Northwest China]. / å ³ä¸­å¹³åŽŸéº¦çŽ‰è½®ä½œä½“ç³»ä½œç‰©ç§¸ç§†ä¸åŒè¿˜ç”°æ¨¡å¼ä¸‹åœŸå£¤æœ‰æœºç¢³å’Œæ— æœºç¢³åº“å˜åŒ–ç‰¹å¾.

To understand the effects of straw return modes on soil carbon pools, we investigated total soil organic carbon (SOC), labile organic carbon fractions, and inorganic carbon (SIC) in different straw return modes at a depth of 0-40 cm under a maize-wheat cropping system in the Guanzhong Plain, Shaanxi, based on an 11-year field experiment. There were five straw return modes, i.e., no return of straw of both wheat and maize (CK), the retention of high wheat stubble plus the return of chopped maize straw (WH-MC), the return of both chopped wheat and maize straw (WC-MC), the retention of high wheat stubble and no return of maize straw (WH-MN), and the return of chopped wheat straw and no return of maize straw (WC-MN). The proportions of SOC storage were significantly higher under the WH-MC and WC-MC treatments than that under the CK by 28.1% and 22.2%, respectively. The proportions of SIC storage were increased by 20.4% and 17.3%, respectively. Compared with the initial value, the increases of sequestered SOC and SIC ranged from -0.84 t·hm-2 to 6.55 t·hm-2, respectively, and from -0.26 t·hm-2 to 8.61 t·hm-2, respectively. The efficiency of sequestration of SOC was 7.5%. To maintain the basic SOC level, the minimum carbon input from straw was 4.65 t·hm-2·a-1. The contents of labile carbon fractions at the 0-20 cm layer increased significantly under the WH-MC and WC-MC treatments compared with those of the control. Results of principal component analysis showed that the changes in soil carbon pools were primarily affected by the amount of straw return. Additionally, the increases in SIC storage could be ascribed to the Ca2+ and Mg2+ ions derived from irrigation water and plant residues that could coprecipitate with the CO2 from SOC mineralization to form CaCO3. In conclusion, our results indicated that the straw return mode that utilized the retention of high wheat stubble and chopped maize straw was sufficient to maintain soil carbon storage and would be the optimal straw-returning strategy for the region.

The complete chloroplast genome sequence of rare and endangered Camellia pubipetala Y. Wan & S. Z. Huang (Theaceae) of South China.

The complete chloroplast genome sequence of rare and endangered Camellia pubipetala Y. Wan & S. Z. Huang (Theaceae) was mentioned in this research. By studying comparatively, we found that the C. pubipetala Y. Wan & S. Z. Huang chloroplast genome was 156,993 bp in length and composed of 86,590 bp LSC, 18,211 bp SSC, and two reverse repeating regions with 26,090 bp. The whole GC content was 37.33%. The genome encoded 116 functional genes, including 80 protein-coding genes, 32 tRNA genes, and 4 rRNA genes. In order to find the phylogenetic relationship of C. pubipetala Y. Wan & S. Z. Huang within Camellia genus, we reconstructed phylogenetic tree. The results indicate that C. pubipetala Y. Wan & S. Z. Huang was closely related to Camellia huana voucher and Camellia ptilosperma.

Comprehensive evaluation of intravitreal conbercept versus half-dose photodynamic therapy for chronic central serous chorioretinopathy.

AIM: To compare the safety and efficacy of conbercept intravitreal injection and half-dose photodynamic therapy (PDT) in treating chronic central serous chorioretinopathy (CSC). METHODS: This study was retrospective. Thirty-seven patients (37 eyes) with chronic CSC received conbercept injections while 57 patients (57 eyes) were treated with half-dose PDT. All subjects were followed in 6mo. Outcome measures included change in best-corrected visual acuity (BCVA), central macular thickness (CMT), subfoveal choroidal thickness (SFCT), and resolution of subretinal fluid (SRF). RESULTS: There was no adverse event observed in either treatment group. At the 6-month follow-up, 26 eyes (70.3%) in the conbercept group and 54 eyes (94.7%) in the half-dose PDT group (P<0.05) reached full resolution of SRF. The mean logarithm of the minimum angle of resolution (logMAR) BCVA significantly improved (P<0.001) in both treatment groups with better outcome at early phase in the half-dose PDT group (2wk, 1, and 2mo, P<0.05). All subjects experienced significant CMT improvement (P<0.001) with no statistical difference between the two groups (P>0.05). The SFCT also improved in all subjects (P<0.001) with better outcome in the half-dose PDT group (P<0.05). CONCLUSION: Both intravitreal conbercept and half-dose PDT are safe to use in treating chronic CSC. By 6mo, both treatment groups are efficacious in improving BCVA, reducing CMT and SFCT, and resolving SRF in eyes with chronic CSC. Half-dose PDT may show better outcome at initial phase of treatment in chronic CSC. Longer follow-up period is necessary to study for long-term effect and safety.

Four-microRNA signature for detection of type 2 diabetes.

BACKGROUND: Sensitive, novel, and accurate biomarkers for the detection of physiological changes in type 2 diabetes (T2DM) at an early stage are urgently needed. AIM: To build a multi-parameter diagnostic model for the early detection of T2DM. METHODS: MiR-148b, miR-223, miR-130a, and miR-19a levels were detected by real-time polymerase chain reaction in serum of healthy controls, individuals with impaired glucose regulation, and T2DM patients. The diagnostic value of miR-148b, miR-223, miR-130a, and miR-19a, alone or in combination, was analyzed. RESULTS: The area under the curve (AUC) of miR-223, which had the best diagnostic value for discriminating the impaired glucose regulation and T2DM groups, was 0.84, and the sensitivity and specificity were 73.37% and 81.37%, respectively. The AUC of the four-miRNA signature was 0.90, and the sensitivity and specificity were 78.82% and 88.23%, respectively. In the validation set, the AUC was 0.88, and the sensitivity and specificity were 78.36% and 87.63%, respectively. CONCLUSION: In summary, we have built a multi-parameter diagnostic model consisting of miR-148b, miR-223, miR-130a, and miR-19a for the detection of T2DM. It may be a potential tool for the early detection of T2DM.

Colonic vitamin D receptor expression is inversely associated with disease activity and jumonji domain-containing 3 in active ulcerative colitis.

BACKGROUND: The expression of jumonji domain-containing 3 (Jmjd3) and trimethylated H3 lysine 27 (H3K27me3) in active ulcerative colitis (UC) and the correlation between vitamin D receptor (VDR) and the Jmjd3 pathway are unknown. AIM: To study the relationship between VDR, Jmjd3 and H3K27me3 in patients with active UC. METHODS: One hundred patients with active UC and 56 healthy controls were enrolled in this study. The patients with active UC were divided into groups according to mild (n = 29), moderate (n = 32) and severe (n = 29) disease activity based on the modified Mayo score. Vitamin D levels were measured by radioimmunoassay. Colonic mucosal tissues from UC patients and controls were collected by colonoscopy. The expression of VDR, Jmjd3 and H3K27me3 in the intestinal mucosa was determined by immunohistochemistry staining. RESULTS: Patients with active UC had lower levels of serum vitamin D (13.7 ± 2.8 ng/mL, P < 0.001) than the controls (16.2 ± 2.5 ng/mL). In the UC cohort, serum vitamin D level was negatively correlated with disease activity (r = -0.323, P = 0.001). VDR expression in the mucosa of UC patients was reduced compared to that in normal tissues (P < 0.001) and negatively correlated with disease activity (r = -0.868, P < 0.001). Similar results for VDR expression were noted in the most serious lesion (defined as UC diseased) and 20 cm proximal to the anus (defined as UC normal) (P < 0.05). Simultaneously, Jmjd3 expression significantly increased in UC patients (P < 0.001), but no difference was found between the different sites in UC patients. H3K27me3 expression in UC patients was significantly down-regulated when compared with normal tissues (P < 0.001), but up-regulated in the mild disease activity group in comparison with the moderate disease activity group of UC patients (P < 0.05). Jmjd3 Level was negatively correlated with the level of VDR (r = -0.342, P = 0.002) and H3K27me3 (r = -0.341, P = 0.002), while VDR level was positively correlated with H3K27me3 (r = 0.473, P < 0.001). CONCLUSION: Serum vitamin D and VDR were inversely correlated with disease activity in active UC. Jmjd3 expression increased in the colonic mucosa of active UC patients and was negatively associated with VDR and H3K27me3 level.

miR-378b Regulates Insulin Sensitivity by Targeting Insulin Receptor and p110α in Alcohol-Induced Hepatic Steatosis.

Insulin resistance has been implicated in alcoholic liver disease. A previous study has shown that microRNAs (miRNAs) play a major role in the production, secretion, and function of insulin. MiRNAs are capable of repressing multiple target genes that in turn negatively regulate various physiological and pathological activities. However, current information on the biological function of miRNAs in insulin resistance is limited. The goal of the present study was to elucidate the role of miR-378b in alcohol-induced hepatic insulin resistance and its underlying mechanism. This study has observed that miR-378b is up-regulated in National Institute on Alcohol Abuse and Alcoholism (NIAAA) alcoholic mouse models as well as in ethanol-induced L-02 cells in vitro. Furthermore, miR-378b overexpression impaired the insulin signaling pathway, and inhibition of miR-378b improved insulin sensitivity in vivo and in vitro. A mechanistic study revealed that IR and p110α are direct targets of miR-378b. Together, these results suggest that miR-378b controls insulin sensitivity by targeting the insulin receptor (IR) as well as p110α and possibly play an inhibitory role in the development of insulin resistance, thereby providing insights into the development of novel diagnostic and treatment methods.

Obeticholic acid prevents carbon tetrachloride-induced liver fibrosis through interaction between farnesoid X receptor and Smad3.

Liver fibrosis results from sustained liver injury and is characterized by inflammation, hepatic stellate cell (HSC) activation, extracellular matrix (ECM) accumulation and liver structure destruction. The Farnesoid-X receptor (FXR) antagonizes toxic liver injury and fibrosis, yet the mechanism in liver fibrosis remains unclear. We investigated the effects of FXR agonist obeticholic acid (OCA) on liver fibrosis in mice. Mice were injected with carbon tetrachloride (CCl4) for 3 weeks or 6 weeks to induce liver fibrosis. OCA (5 mg/kg) or PBS is administered daily during CCl4-treatment. At sacrifice, biochemical parameters and fibrosis were assessed. Pretreatment with OCA alleviated hepatic injury in 6 weeks group but not in 3 weeks group of CCl4 liver cirrhosis. At same time, pretreatment with OCA exhibit a dramatic protection of liver fibrosis in both 3 weeks group and 6 weeks group. Further experiments found that OCA pretreatment inhibited α-SMA expression and the activation of hepatic pSmad3 in 3 weeks group and 6 weeks group of CCl4-induced liver cirrhosis. Moreover, OCA activated FXR nuclear translocation and increased the interaction between liver FXR and pSmad3. This led to the discovery of a novel role for FXR in regulating fibrosis through interaction with pSmad3. Our data suggest that CCl4-induced liver fibrosis is protected by OCA through interaction between farnesoid X receptor and Smad3.

Obeticholic acid differentially regulates hepatic injury and inflammation at different stages of D-galactosamine/lipopolysaccharide-evoked acute liver failure.

The farnesoid X receptor (FXR) is a ligand-activated transcription factor that regulates genes involved in bile acid metabolism. Accumulating data demonstrate that FXR has an anti-inflammatory activity. The present study aimed to investigate the effect of obeticholic acid (OCA), a novel synthetic FXR agonist, on D-galactosamine (GalN)/lipopolysaccharide (LPS)-evoked acute liver injury. All mice except controls were intraperitoneally injected with GalN (300 mg/kg) plus LPS (2.5 µg/kg). Some mice were pretreated with OCA (10 mg/kg) 48, 24 and 1 h before GalN/LPS. As expected, pretreatment with OCA alleviated hepatocyte apoptosis at early and middle stages of GalN/LPS-induced acute liver failure. By contrast, pretreatment with OCA augmented hepatic injury and inflammatory cell infiltration at middle stage of GalN/LPS-induced acute liver failure. Additional experiment found that OCA inhibited hepatic NF-κB activation at early and middle stages of GalN/LPS-induced acute liver failure. Interestingly, OCA inhibited hepatic proinflammatory cytokine tnf-α and il-6 but upregulated hepatic anti-inflammatory cytokine il-10 at early stage of GalN/LPS-induced acute liver failure. By contrast, OCA suppressed hepatic anti-inflammatory cytokine tgf-ß and il-10 at middle stage of GalN/LPS-induced acute liver injury. These results suggest that FXR agonist OCA differentially regulates hepatic injury and inflammation at different stages of GalN/LPS-evoked acute liver failure.