Overexpression of circZNF720 Inhibits Hepatocellular Carcinoma Progression by Regulating miR-421/MAPK9.

Hepatocellular carcinoma (HCC) is characterized by high incidence, high death rate and poor long term prognosis. Abnormal expression of circular RNA (circRNA) has been demonstrated to be closely associated with malignant progression of HCC. However, the effect of circZNF720 on HCC is largely incompletely understood. This study sought to explore the effect of circZNF720 on the progression of HCC by CCK-8, transwell, and flow cytometry experiments. The prognosis of circZNF720 on patients was analyzed by Kaplan-Meier curve. Then, the regulatory mechanisms among circZNF720, miR-421, and MAPK9 were identified by qRT-PCR, dual-luciferase reporter assay, and RIP analysis, respectively. The outcomes of this study disclosed that circZNF720 was lowly expressed in HCC, and this low expression was strongly linked with a poor prognosis for HCC patients. Overexpression of circZNF720 inhibited the proliferation, migration, and invasion of cells, and increased the apoptosis of cells. Mechanistic studies revealed that circZNF720 targeted miR-421 and regulated the development of HCC by acting as a sponge for miRNAs. In addition, MAPK9 was a downstream target of miR-421, and circZNF720 introduction hampered HCC progression by upregulating MAPK9 expression through sponging miR-421. In conclusion, circZNF720 restrained HCC progression by targeting miR-421/MAPK9. This study provides a novel target for the treatment of HCC.

Sorafenib plus drug-eluting bead transarterial chemoembolization for early intrahepatic stage-progressed advanced hepatocellular carcinoma refractory to conventional transarterial chemoembolization.

PURPOSE: To investigate the effectiveness and safety of the combination of sorafenib and drug-eluting bead transarterial chemoembolization (DEB-TACE) in the treatment of early intrahepatic stage-progressed advanced hepatocellular carcinoma (ISPA-HCC). METHODS: This study was approved by the ethics committees of six tertiary medical centers in China. Between October 2017 and October 2020, 213 patients with advanced HCC received either sorafenib combined with on-demand DEB-TACE (DTS group, n = 103) or sorafenib monotherapy (S group, n = 110). Overall survival (OS), time to progression (TTP), local tumor response, and adverse events (AEs) were compared between the two groups. RESULTS: The incidences of nause/vomiting, abdonimal pain, hyperbilirubinemia, fever and ALT/AST increasing were higher in the DTS group. The post-treatment partial response, objective response, and disease control rates were significantly higher in the DTS group than in the S group (51.5% vs. 23.6%; 56.3% vs. 25.5%; 77.7% vs. 56.4%, respectively). The median OS was significantly longer in the DTS group than in the S group [16.3 vs. 10.0 months; hazard ratio (HR) = 0.43; P < 0.001], as was the TTP (6.7 vs. 4.3 months; HR = 0.60; P = 0.001). In the DTS group, patients who received ≥ 2 sessions of DEB-TACE benefited more than those who received two sessions of DEB-TACE. Multivariate analysis revealed that the α-fetoprotein level and treatment allocation were independent predictors of OS and TTP. CONCLUSION: The combination of sorafenib and DEB-TACE is safe and effective for the treatment of early ISPA-HCC.

Idarubicin-Loaded DEB-TACE plus Lenvatinib versus Lenvatinib for patients with advanced hepatocellular carcinoma: A propensity score-matching analysis.

AIMS: To investigate the efficacy and safety of lenvatinib and idarubicin-loaded drug-eluting beads transarterial chemoembolization (IDADEB-TACE) in primary advanced hepatocellular carcinoma (HCC). METHODS: This retrospective study included patients with primary advanced HCC who received either lenvatinib monotherapy or lenvatinib plus IDADEB-TACE as first-line treatment from September 2019 to September 2020 at three institutes. Overall survival (OS), time to progression (TTP), objective response rate (ORR), and adverse events were compared. Propensity score-matching was used to reduce the influence of confounding factors on the outcomes. RESULTS: The study reviewed 118 patients who received lenvatinib plus IDADEB-TACE (LIDA group) and 182 who received lenvatinib alone (LEN group). After propensity score-matching, 78 pairs of patients remained. Compared to patients in the LEN group, those in the LIDA group had better post-treatment ORR (57.7% vs. 25.6%, p < 0.001, respectively), median OS and TTP (15.7 vs. 11.3 months, hazard ratio [HR] = 0.50, p < 0.001; 8.0 vs. 5.0 months, HR = 0.60, p = 0.003, respectively), 6- and 12-month OS rates (88.5% vs. 71.4%; 67.6% vs. 43.4%, respectively), and progression-free rates at 6 and 12 months (60.3% vs. 42.3%; 21.1% vs. 10.3%, respectively). Vascular invasion, α-fetoprotein level, and treatment type were independent OS predictors, and vascular invasion and treatment type were independent TTP predictors. Incidences of nausea/vomiting, fever, abdominal pain, and increased ALT/AST were higher in the LIDA group than in the LEN group. CONCLUSIONS: Lenvatinib plus IDADEB-TACE is well-tolerated and more effective than lenvatinib monotherapy in patients with advanced HCC.

Identifying optimal candidates for post-TIPS patients with HCC undergoing TACE: a multicenter observational study.

OBJECTIVE: To develop a prognostic model for post-transjugular intrahepatic portosystemic shunt (TIPS) patients with hepatocellular carcinoma (HCC) beyond the Milan criteria treated by transarterial chemoembolization (TACE). DESIGN: Between January 2013 and January 2020, 512 patients with HCC beyond the Milan criteria who underwent TACE after TIPS were retrospectively recruited from 15 tertiary centers. Patients were randomly sorted into a training set (n = 382) and a validation set (n = 130). Medical data and overall survival were assessed. A prediction model was developed using multivariate Cox regression analyses. Predictive performance and discrimination were evaluated and compared with other prognostic models. RESULTS: Vascular invasion, log10(AFP), 1/creatinine, extrahepatic spread, and log10(ALT) were the most significant prognostic factors of survival. These five parameters were included in a new VACEA score. This score was able to stratify patients in the training set into four distinct risk grades whose median overall survival were 25.2, 15.1, 8.9, and 6.2 months, respectively. The 6-month, 1-year, 2-year, and 3-year AUROC values and C-index of the VACEA model were 0.819, 0.806, 0.779, 0.825, and 0.735, respectively, and higher than those of other seven currently available models in both the training and validation sets, as well as in different subgroups. CONCLUSION: The VACEA score could stratify post-TIPS patients with HCC beyond the Milan criteria treated by TACE and help to identify candidates who benefit from this treatment. KEY POINTS: • Vascular invasion, AFP, creatinine, extrahepatic spread, and ALT were independent significant prognostic factors of survival for HCC patients who underwent TACE after TIPS. • Our new model, named VACEA score, can accurately predict prognosis at the individual level and stratify patients into four distinct risk grades. • The VACEA model showed better prognostic discrimination and calibration than other current TACE-/TIPS-specific models Graphical abstract.

Lenvatinib Combined With Transarterial Chemoembolization as First-Line Treatment for Advanced Hepatocellular Carcinoma: A Phase III, Randomized Clinical Trial (LAUNCH).

PURPOSE: Lenvatinib (LEN) is a first-line therapy for patients with advanced hepatocellular carcinoma (HCC); however, it has shown modest survival benefits. Therefore, we aimed to compare clinical outcomes of LEN combined with transarterial chemoembolization (LEN-TACE) versus LEN monotherapy in patients with advanced HCC. MATERIALS AND METHODS: This was a multicenter, randomized, open-label, parallel group, phase III trial. Patients with primary treatment-naive or initial recurrent advanced HCC after surgery were randomly assigned (1:1) to receive LEN plus on-demand TACE (LEN-TACE) or LEN monotherapy. LEN was initiated within 3 days after random assignment (initial dose: 12 mg once daily for patients ≥ 60 kg; 8 mg once daily for patients < 60 kg). TACE was initiated one day after LEN initiation. The primary end point was overall survival (OS). RESULTS: Between June 2019 and July 2021, a total of 338 patients underwent random assignment at 12 centers in China: 170 to LEN-TACE and 168 to LEN. At a prespecified event-driven interim analysis after a median follow-up of 17.0 months, the median OS was significantly longer in the LEN-TACE group (17.8 v 11.5 months; hazard ratio, 0.45; P < .001). The median progression-free survival was 10.6 months in the LEN-TACE group and 6.4 months in the LEN group (hazard ratio, 0.43; P < .001). Patients in the LEN-TACE group had a higher objective response rate according to the modified RECIST (54.1% v 25.0%, P < .001). Multivariable analysis revealed that portal vein tumor thrombus and treatment allocation were independent risk factors for OS. CONCLUSION: The addition of TACE to LEN improves clinical outcomes and is a potential first-line treatment for patients with advanced HCC.

Drug-eluting beads TACE is safe and non-inferior to conventional TACE in HCC patients with TIPS.

OBJECTIVES: This study aims to compare the safety and effectiveness between transarterial chemoembolization (TACE) with drug-eluting beads (DEB-TACE) and conventional TACE (cTACE) using lipiodol-based regimens in HCC patients with a transjugular intrahepatic portosystemic shunt (TIPS). METHODS: This retrospective study included patients with patent TIPS who underwent TACE from January 2013 to January 2019 that received either DEB-TACE (DEB-TACE group, n = 57) or cTACE (cTACE group, n = 62). The complications, liver toxicity, overall survival (OS), time to progression (TTP), and objective response rate (ORR) were compared between the groups. RESULTS: Altogether, 119 patients (50 ± 11 years, 107 men) were evaluated. The incidence of adverse events, including abdominal pain within 7 days (45.6% vs 79.0%, p < 0.001) and hepatic failure within 30 days (5.3% vs 19.4%, p = 0.027), were significantly lower in the DEB-TACE group than in the cTACE group. Compared to the cTACE group, the DEB-TACE group also showed mild liver toxicities in terms of increased total bilirubin (8.8% vs 22.6%), alanine aminotransferase (5.3% vs 21.0%), and aspartate aminotransferase (10.5% vs 29.0%) levels. The DEB-TACE group had better ORR than the cTACE group (70.2% vs 50.0%). The median OS and TTP were longer in the DEB-TACE group (11.4 vs 9.1 months, hazard ratio [HR] = 2.46, p < 0.001; 6.9 vs 5.2 months, HR = 1.47, p = 0.045). Multivariable analysis showed that α-fetoprotein levels, Barcelona clinic liver cancer stage, and treatment allocation were independent predictors of OS. CONCLUSION: DEB-TACE is safe and effective in HCC patients with a TIPS and is potentially superior to cTACE in terms of complications, liver toxicities, OS, TTP, and ORR. KEY POINTS: • DEB-TACE is safe and effective in HCC patients after a TIPS procedure. • DEB-TACE improves overall survival, objective response rate, and liver toxicities and is non-inferior to cTACE in terms of time to progression. • DEB-TACE might be a potential new therapeutic option for HCC patients with TIPS.

Electrophysiology as a prognostic indicator of visual recovery in diabetic patients undergoing cataract surgery.

PURPOSE: Visual outcomes after cataract surgery in diabetic patients with retinal or visual pathway disease are difficult to predict as the fundus may be obscured, and assessment of visual potential is challenging. This study assessed the value of visual electrophysiology as a prognostic indicator of visual recovery in diabetic patients with cataract, prior to cataract surgery. METHODS: Forty-one diabetic patients (aged 52-80; 74 eyes) and 13 age-matched non-diabetic control patients (21 eyes) were examined prior to cataract surgery. Pre-surgical examinations included best-corrected visual acuity (BCVA), slit-lamp bio-microscopy, ISCEV-standard full-field electroretinography (ffERG), and flash visual evoked potential (flash VEP) testing. Electrophysiological assessments included quantification of the DA and LA ERG, oscillatory potentials (OPs; OP1, OP2, OP3, OP4) and flash VEP P1, P2, and P3 components. Post-operative BCVA was measured in all cases and the diabetic patients grouped according to the severity of visual acuity loss: mild (logMAR ≤ 0.1), moderate (0.1 < logMAR < 0.5), or severe (logMAR ≥ 0.5). A fourth group included those without diabetes. The pre-surgical electrophysiological data was compared between the four groups by analysis of variance. RESULTS: The severity of post-surgical visual acuity loss in the diabetic patients was classified as mild (N=22 eyes), moderate (N=31 eyes), or severe (N=21 eyes). In the group without diabetes, post-surgical visual impairment was classified as mild (N=21 eyes). The pre-operative DA 10.0 ERG a-wave amplitudes, DA 3.0 ERG OP2 amplitudes, and the LA 3.0 a- and b-wave amplitudes showed best significant differences among the four groups. The flash VEP did not show significant difference between groups. CONCLUSION: Electrophysiological assessment of diabetic patients with cataract can provide a useful measure of retinal function. Full-field ERG components, including the DA 10.0 ERG a-wave, DA 3.0 ERG OP2 component, and the LA 3.0 a- and b-wave amplitudes, are of prognostic value in predicting post-surgical visual acuity, and may inform the surgical management of cataract patients with diabetes.

Sutured Intrascleral Posterior Chamber Intraocular Lens Fixation with Ciliary Sulcus Location Guided by Ultrasonic Biological Microscopy: A Retrospective Analysis of Anatomical and Refractive Outcome.

PURPOSE: To report the outcome of sutured intrascleral posterior chamber intraocular lens (PC IOL) fixation with ciliary sulcus location guided by ultrasonic biological microscopy (UBM). METHODS: Patients who underwent a sutured intrascleral PC IOL fixation were reviewed and divided into four groups. In group 1, the traditional sulcus fixation (2 mm from limbus) of IOL was performed. In groups 2, 3, and 4, UBM was performed before surgery to locate the position of the ciliary sulcus as the haptics insertion position. IOL power was selected by decreasing the calculated value of the IOL power by 1.0 D, 1.0 D, 0.5 D, and 0.0 D, respectively. RESULTS: Sixty-one patients (63 eyes) were included in the four groups. After 4.1 ± 3.0 months' follow-up, the postsurgery spherical equivalent (SE) was 0.73 ± 1.86, 0.71 ± 0.84, 1.14 ± 0.45, and 0.07 ± 0.89 diopters (D), respectively. Statistical significance was reached for the postsurgery SE with target refraction between group 1 (p = 0.027, <0.05), group 2 (p = 0.003, <0.01), and group 3 (p = 0.017, <0.05). No significant difference existed for the postsurgery SE with target refraction in group 4 (p = 0.779, >0.05), and the postsurgery SE in group 4 was the nearest to target refraction. CONCLUSION: Intrascleral PC IOL fixation guided by UBM is helpful for locating the ciliary sulcus and satisfactory visual outcomes with a predictable IOL power calculation.

MicroRNA-191 targets CCAAT/enhanced binding protein ß and functions as an oncogenic molecule in human non-small cell lung carcinoma cells.

The aberrant expression of microRNAs (miRs) may be involved in tumor growth and progression in human non-small cell lung carcinoma (NSCLC). The present study aimed to investigate the potential roles of miR-191 in NSCLC. Western blotting and reverse transcription-quantitative polymerase chain reaction were performed to assess protein and/or mRNA levels. Scratch wound healing and transwell assays were performed to determine the NSCLC cell migration and invasion. A luciferase demonstrated that CCAAT/enhanced binding protein ß (C/EBPß) was a target of miR-191. Previously, miR-191 has been reported to act as an oncogenic player in multiple human cancers. C/EBPß has been identified as a target gene of miR-191; however, the roles and underlying mechanisms of miR-191 associated with the regulation of tumor invasion in NSCLC remain unknown. In the present study, it was demonstrated that miR-191 expression levels were higher in human NSCLC tumors compared with in normal adjacent tissue and elevated miR-191 expression levels were closely associated with tumor node metastasis stage in patients with NSCLC. Furthermore, transfection with miR-191 mimic inhibited C/EBPß expression at the mRNA and protein levels and promoted A549 cell migration and invasion. C/EBPß was reported to be the direct target gene of miR-191 using a dual luciferase reporter assay. Finally, C/EBPß siRNA can mimic the effects of miR-191. These findings indicated that miR-191 may function as an oncogene in NSCLC, at least partially due to its negative regulatory on C/EBPß.

Apatinib Combined With Transarterial Chemoembolization in Patients With Hepatocellular Carcinoma and Portal Vein Tumor Thrombus: A Multicenter Retrospective Study.

PURPOSE: Studies focusing on the effects of combined transcatheter arterial chemoembolization (TACE) + the tyrosine kinase inhibitor apatinib in the treatment of patients with hepatocellular carcinoma (HCC), with the location and extent of portal vein tumor thrombus (PVTT) assessed as the main variable, are rare. This multicenter, retrospective, controlled study was performed to compare the efficacy and tolerability of TACE + apatinib and TACE alone in patients with HCC and PVTT. METHODS: We retrospectively analyzed data from patients with nonresectable HCC and PVTT who underwent treatment with TACE + apatinib or TACE alone between January 2015 and January 2016. Outcomes in patients who underwent TACE + apatinib were compared with the outcomes of patients who underwent TACE alone, by using the Kaplan-Meier method, according to PVTT type: PVTT in the main portal vein (type A), PVTT in the first-order portal vein branch (type B), and PVTT in second- or lower-order portal vein branches (type C). FINDINGS: One hundred eighty-eight patients were included in the analysis; 85 underwent treatment with TACE + apatinib and 103 underwent treatment with TACE. TACE + apatinib was associated with a significantly greater median survival compared with TACE alone in patients with PVTT type B (12.2 vs 7.5 months; P < 0.001) or type C (13.7 vs 7.2 months; P = 0.006). Along with treatment strategies and α-fetoprotein, the absence of main PVTT was an independent factor predictive of survival on uni- and multivariate analysis. Apatinib-related grade 3 adverse events occurred in 27 patients (31.8%). IMPLICATIONS: TACE + apatinib can be of potential benefit to patients with advanced HCC with tumor thrombus in the first- and lower-order portal vein branches. Adverse events with apatinib need to be monitored during application, despite the manageable appearance.

Long non-coding RNA XIST promotes cell growth by regulating miR-139-5p/PDK1/AKT axis in hepatocellular carcinoma.

Abnormal expression of long non-coding RNA often contributes to unrestricted growth of cancer cells. Long non-coding RNA XIST expression is upregulated in several cancers; however, its modulatory mechanisms have not been reported in hepatocellular carcinoma. In this study, we found that XIST expression was significantly increased in hepatocellular carcinoma tissues and cell lines. XIST promoted cell cycle progression from the G1 phase to the S phase and protected cells from apoptosis, which contributed to hepatocellular carcinoma cell growth. In addition, we revealed that there was reciprocal repression between XIST and miR-139-5p. PDK1 was identified as a direct target of miR-139-5p. We proposed that XIST was responsible for hepatocellular carcinoma cell proliferation, and XIST exerted its function through the miR-139-5p/PDK1 axis.

Bilateral cataract surgery in a 56-year-old man following presbyopia laser in situ keratomileusis: A case report.

We describe a case of bilateral cataract surgery in a 56-year-old man following presbyopia laser in situ keratomileusis. The preoperative refraction was -2.00 in the right eye and -0.75 × 105 in the left eye. On the last examination, the uncorrected distance visual acuity was 20/80 that can be corrected to 20/20 in the right eye with a refraction of -2.25 and 20/20 in the left eye, whereas the visual acuity for reading was 20/40 in the right eye and 20/80 in the left eye with a refraction of +2.25. His monovision surgery design of previous cornea surgery was also taken into consideration for the phacoemulsification and posterior chamber intraocular lens (IOL) implantation. Two-step surgery is helpful for predicting an accurate IOL degree.

Subretinal transplantation of retinal pigment epithelium overexpressing fibulin-5 inhibits laser-induced choroidal neovascularization in rats.

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Choroidal neovascularization (CNV) is the abnormal angiogenesis that causes severe visual loss in AMD. Fibulin-5 (Fbln5), which functions as an angiogenesis inhibitor, plays an important role in the pathogenesis of AMD. Here, we investigated whether subretinal transplantation of Fbln5-overexpressing retinal pigment epithelial (RPE) cells can inhibit CNV in vivo. Adult Long-Evans rats were used in this study. CNV was induced by laser photocoagulation. One week after laser-induced CNV, RPE cells expressing pZlen-Fbln5-IRES-GFP or the control pZlen-IRES-GFP vectors were transplanted into the subretinal space of the right and left eyes, respectively. CNV was evaluated using fundus photography, fundus fluorescein angiography (FFA), and hematoxylin and eosin staining. We found that CNV occurred at 1 week after photocoagulation, reaching peak activity at 3 weeks and remaining at a high level at 4-5 weeks after photocoagulation. Transplanted RPE cells survived for at least 4 weeks and migrated toward the retina. Subretinal transplantation of Fbln5-overexpressing RPE cells resulted in a significant reduction in the total area of leakage and the number of leakage spots compared with transplantation of RPE cells expressing only green fluorescent protein. Our findings suggest that subretinal transplantation of Fbln5-overexpressing RPE cells inhibits laser-induced CNV in rats and thus represents a promising therapy for the treatment of AMD.

[Prevalence and causes of blindness and moderate and severe visual impairment among adults aged 50 years or above in Yongchuan District of Chongqing City: the China Nine-Province survey].

OBJECTIVE: To investigate the prevalence and causes of blindness and moderate and severe visual impairment among adults aged 50 years or above in Yongchuan of Chongqing City, China. METHODS: It was a population-based cross-section study.Geographically defined cluster sampling was used in randomly selecting 5663 individuals aged ≥ 50 years in Yongchuan District. The survey was preceded by a pilot study where operational methods were refined and quality assurance evaluation was carried out. All participants were enumerated through village registers followed door-to-door visits.Eligible individuals were invited to receive visual acuity measurement and eye examination. Prevalence of blindness and moderate and severe visual impairment was calculated according to different age, gender or education. And the reasons of blindness were analyzed.Statistical analyses were performed using Stata/SE Statistical Software, release 9.0. Chi-square test was used to investigate the association of age, gender and education with presenting and best corrected visual acuity. RESULTS: Five thousands six hundreds and sixty-three individuals were enumerated and 5390 persons were examined, the response rate was 95.18%. Based on the criteria of World Health Organization visual impairment classification in 1973, the prevalence of blindness and moderate and severe visual impairment defined as best corrected visual acuity was 2.12% (114/5390) and 5.40% (291/5390) respectively. The prevalence of blindness and moderate and severe visual impairment defined as presenting visual acuity was 2.49% (134/5390) and 10.71% (577/5390) respectively. The prevalence of blindness and moderate and severe visual impairment was higher in aged (trend χ(2) = 951.32, P = 0.000) , female (χ(2) = 33.35, P = 0.000) and illiterate (trend χ(2) equals; 141.32, P = 0.000) persons. Cataract was still the first leading cause of blindness and visual impairment.Un-corrected refractive error also was the main cause of visual impairment. CONCLUSIONS: The prevalence of blindness and moderate and severe visual impairment is relatively higher among older adults aged 50 years or above in Yongchuan District. The first leading cause of blindness and visual impairment is still cataract.

Overexpression of fibulin-5 in retinal pigment epithelial cells inhibits cell proliferation and migration and downregulates VEGF, CXCR4, and TGFB1 expression in cocultured choroidal endothelial cells.

PURPOSE OF THE STUDY: Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss. Fibulin-5 (FBLN5) plays a pleiotropic role in the pathogenesis of AMD. We examined whether the in vitro overexpression of FBLN5 in retinal pigment epithelial (RPE) cells alters the proliferation and migration of cocultured choroidal endothelial cells (CECs) and explored the possible mechanisms involved. MATERIALS AND METHODS: A recombinant lentiviral vector carrying the Fbln5 gene was generated to transduce rat RPE cells. The expression of FBLN5 in transduced RPE cells was detected by quantitative real-time PCR and Western blot. The transduced RPE cells were then cocultured with rhesus macaque CECs in a Transwell coculture system. The impact of overexpression of FBLN5 in RPE cells on CEC proliferation and migration was assessed, as well as the impact on the mRNA expressions of vascular endothelial growth factor (VEGF), C-X-C chemokine receptor type 4 (CXCR4), and transforming growth factor ß1 (TGFB1). RESULTS: Our results showed that a recombinant lentivirus carrying the Fbln5 gene, which could induce overexpression of FBLN5 in RPE cells, was successfully generated. Overexpression of FBLN5 in RPE cells inhibited cell proliferation and migration and downregulated the mRNA expressions of VEGF, CXCR4, and TGFB1 in cocultured CECs. CONCLUSIONS: These findings suggest that FBLN5 may interfere with choroidal neovascularization by downregulating VEGF, CXCR4, and TGFB1 expression and inhibiting CEC proliferation and invasion, intensifying interest in FBLN5 as a target for therapeutic intervention in neovascular AMD.

Ytterbium and trace element distribution in brain and organic tissues of offspring rats after prenatal and postnatal exposure to ytterbium.

Lanthanides, because of their diversified physical and chemical effects, have been widely used in a number of fields. As a result, more and more lanthanides are entering the environment and eventually accumulating in the human body. Previous studies indicate that the impact of lanthanides on brain function cannot be neglected. Although neurological studies of trace elements are of paramount importance, up to now, little data are provided regarding the status of micronutritional elements in rats after prenatal and long-term exposure to lanthanide. The aim of this study is to determine the ytterbium (Yb) and trace elements distribution in brain and organic tissues of offspring rats after prenatal and long-term exposure to Yb. Wistar rats were exposed to Yb through oral administration at 0,0.1, 2, and 40 mg Yb/kg concentrations from gestation day 0 through 5 mo of age. Concentrations of Yb and other elements (Mg, Ca, Fe, Cu, Mn, and Zn) in the serum, liver, femur, and brain regions (cerebral cortex, hippocampus, cerebellum, and the rest) of offspring rats at the age of 0 d, 25 d, and 5 mo were analyzed by inductively coupled plasma-mass spectrometry. The accumulation of Yb in the brain, liver, and femur is observed; moreover, the levels of Fe, Cu, Mn, Zn, Ca, and Mg in the brain and organic tissues of offspring rats are also altered after Yb exposure. This disturbance of the homeostasis of trace elements might induce adverse effects on normal physiological functions of the brain and other organs.

Nicotine attenuates beta-amyloid-induced neurotoxicity by regulating metal homeostasis.

Nicotine reduces beta-amyloidosis and has a beneficial effect against Alzheimer's disease (AD), but the underlying mechanism is not clear. The abnormal interactions of beta-amyloid (Abeta) with metal ions such as copper and zinc are implicated in the process of Abeta deposition in AD brains. In the present study, we investigated the effect of nicotine on metal homeostasis in the hippocampus and cortex of APP(V717I) (London mutant form of APP) transgenic mice. A significant reduction in the metal contents of copper and zinc in senile plaques and neuropil is observed after nicotine treatment. The densities of copper and zinc distributions in a subfield of the hippocampus CA1 region are also reduced after nicotine treatment. We further studied the mechanism of nicotine-mediated effect on metal homeostasis by using SH-SY5Y cells overexpressing the Swedish mutant form of human APP (APPsw). Nicotine treatment decreases the intracellular copper concentration and attenuates Abeta-mediated neurotoxicity facilitated by the addition of copper, and these effects are independent of the activation of nicotinic acetylcholine-receptor. These data suggest that the effect of nicotine on reducing beta-amyloidosis is partly mediated by regulating metal homeostasis.

Neurotoxicological consequence of long-term exposure to lanthanum.

Lanthanides, because of their diversified physical and chemical effects, have been widely used in a number of fields. As a result, more and more lanthanides are entering into the environment and eventually accumulated in human body. Recently, a new medicine, lanthanum carbonate (Fosrenol), has been used to treat chronic renal failure (CRF), and the dosage is much higher than the daily intake of lanthanides. However, the effects of lanthanides on human body, especially on the central nervous system, are still unclear. The aim of this study was to determine whether long-term lanthanum exposure results in persistent alternations in nervous system function. Wistar rats were exposed to lanthanum chloride (LaCl(3)) through oral administration at 0, 0.1, 2 and 40mg/kg concentration from 4 weeks through 6 months of age. Morris water maze test showed that lanthanum exposure at 40mg/kg could significantly impair the behavioral performance. To fully investigate the neurotoxicological consequence of lanthanum exposure, brain elemental distributions and neurochemicals were also investigated. The distributions of brain elements such as Ca, Fe and Zn were significantly altered after lanthanum exposure. Moreover, 40mg/kg LaCl(3) significantly inhibited the activity of Ca(2+)-ATPase; the function of the central cholinergic system was also noticeably disturbed and the contents of some monoamines neurotransmitters were significantly decreased. These findings indicate that chronic exposure to lanthanum could possibly impair the learning ability and this deficit may be possibly attributed to the disturbance of the homeostasis of trace elements, enzymes and neurotransmitter systems in brain. Therefore, the application of lanthanide, especially in pharmacology, should be cautious.

Long-term effects of lanthanum intake on the neurobehavioral development of the rat.

The effects of subchronic exposure to lanthanum on rats' physical and neurobehavioral development were investigated. Wistar rats were exposed to lanthanum through oral administration at 0, 0.1, 2, and 40 mg/kg concentrations from gestation day 0 through 5 months of age. Prior to weaning of the pups, physical parameters and neurobehaviors were assessed, including body weight gain, pinna detachment, eye opening, surface righting reflex and swimming endurance. At 30 days of age, DNA concentration and protein/DNA ratio of the whole brain were determined. At 150 days of age, the Morris water maze test was carried out to study the memory and learning abilities of the rats. Differences were found in the body weight gain, surface righting reflex and swimming endurance. Moreover, lanthanum exposure significantly altered the DNA concentration and Protein/DNA in brain. The Morris water maze test showed that lanthanum exposure at 40 mg/kg significantly impaired memory and learning abilities. These findings indicate that lanthanum is a potential behavior teratogen. The information provided by this work should be considered in future applications of lanthanides.

Accumulation and distribution of samarium-153 in rat brain after intraperitoneal injection.

It is well known that rare earth elements (REEs) have come into extensive use in a number of fields. As a result, REEs are becoming closely related to human's daily life. However, until now, the distributions of REEs in the brain are not yet very clear. In this study, Sprague-Dawley male rats were intraperitoneally injected with 0.25 mL of (153)SmCl(3) solution (containing 10 microg Sm). The brains were perfused with saline to minimize the blood influence. The radioactivities of (153)Sm in the five brain regions (hypothalamus, cerebellum, hippocampus, corpus striatum, and cerebral cortex) were counted. The results suggested that Sm did enter into the brain. Although only about 0.0003% of the given dose was accumulated in the brain, Sm seemed to be remain in the brain for a long time. The highest amounts and lowest concentrations of (153)Sm were found in the cerebral cortex, and the highest concentrations of (153)Sm were found in the hypothalamus.