Population pharmacokinetics and pharmacogenetics of apatinib in adult cancer patients.

AIMS: Apatinib is widely used in Chinese cancer patients. As the in vivo drug disposition of apatinib has large individual differences, adverse events are prone to occur. Cytochrome P450 (CYP)3A5 and cancer types maybe the main factors affecting this individual differences. The objective of our study was to establish a population pharmacokinetics (PK) model of apatinib in adult cancer patients, and to explore optimal dosage regimens for individualized treatment. METHODS: Adult patients with various types of cancer treated with apatinib were enrolled. The concentration of apatinib in plasma was determined by high-performance liquid chromatography-tandem mass spectrometry. CYP3A5 genotype was determined using TaqMan allelic discrimination technique. The population PK model was developed by NONMEM V7.4. The dosing regimen was optimized based on Monte Carlo simulations. RESULTS: A population PK model of apatinib in adult cancer patient was established. CYP3A5 genotype and systemic cancer type (digestive system cancers, nondigestive system cancers) were the most significant covariates for PK parameters. Patients with CYP3A5*1 expressers (CYP3A5*1/*1 and CYP3A5*1/*3) had lower apparent clearance and apparent volume of distribution than patients who do not express CYP3A5*1 (CYP3A5*3/*3). Patients with nondigestive system cancer had higher apparent volume of distribution and absorption rate constant than digestive system cancer. The results of dose simulation suggest that the apatinib dose in patients who do not express CYP3A5*1 should be 33.33-50.00% higher than that in CYP3A5*1 expressers. CONCLUSIONS: A population PK model of apatinib in adult cancer patients was established. CYP3A5 genotype and systemic cancer type had concurrent effects on PK parameters. CYP3A5 patients who do not express CYP3A5*1 required higher doses.

Identification of Versican as an Independent Prognostic Factor in Uveal Melanoma.

OBJECTIVE: To assess the role of versican (VCAN) in uveal melanoma (UVM) from its expression, prognostic value and biological function. METHODS: The general profile of VCAN mRNA and protein expression levels were obtained using bioinformatic approaches. Then, UALCAN database was adopted to examine the association of VCAN mRNA expression and clinical factors in UVM. The prognostic value of VCAN was assessed by UALCAN, GEPIA and TISIDB databases. Besides, Cox regression analysis was performed to predict the independent prognostic factors for UVM. Further, functional enrichment analysis was conducted to reveal the biological functions of VCAN involved in UVM through DAVID, Cytoscape and GSEA analyses. RESULTS: VCAN showed a relative low expression level in normal eye but was highly expressed in UVM cell lines. Tumor histology and stage in UVM were significantly related to VCAN mRNA expression (all P <0.05). Besides, high VCAN mRNA expression led to unfavorable prognosis of UVM patients, especially in female patients and those aged <60 years (all P <0.05). Cox regression analysis indicated that VCAN mRNA expression was an independent prognostic factor for overall survival in UVM. Enrichment analysis suggested that VCAN was mainly involved in cytokine-cytokine receptor interaction, chemokine signaling pathway and T cell receptor signaling pathway (all P <0.05). Meanwhile, hyaluronic acid was revealed to be a potential drug for the UVM treatment. CONCLUSION: VCAN served as an independent prognostic factor for UVM. Further analysis found that VCAN was positively correlated with metastasis-related pathway, which might imply the metastasis risk of UVM. Our study initially revealed the vital role of VCAN in the process of UVM and provided a therapeutic target for UVM treatment.

Case Report: An Adult Patient With Deficiency of Adenosine Deaminase 2 Resembled Unilateral Frosted Branch Angiitis.

Purpose: Deficiency of adenosine deaminase 2 (DADA2) is a rare autosomal recessive systemic autoinflammatory disorder. We describe a rare case of an adult patient with DADA2 who presented with unilateral frosted branch angiitis (FBA) combined with branch retinal vein occlusion and panuveitis. Method: This paper is a clinical case report. Results: A 31-year-old male patient complained of blurred vision in his right eye for 2 days. His fundus examination showed FBA combined with branch retinal vein occlusion and panuveitis. He had a medical history of intermittent and recurrent fever, skin rash and aphthous ulcer for 5 years, and lacunar infarction for 1 month. Laboratory examinations showed hypogammaglobulinemia and mild prolonged activated partial thromboplastin time (APTT). Brain magnetic resonance imaging (MRI) revealed old lacunar infarction in the right basal ganglia and the lateral ventricle and fresh lacunar infarction in the right pons, respectively. The perivascular sheathing of FBA and macular edema were resolved after steroid administration and treatment of intravitreal anti-VEGF injection. During the period of follow-up, the patient subsequently suffered from recurrence of strokes, abnormality of coagulation function, sudden hearing loss of the left ear, and diplopia. His gene sequencing results demonstrated several deletion mutations in ADA2, and the diagnosis of DADA2 was eventually confirmed. Conclusions: FBA represents a very rare ocular feature of DADA2 and may in some cases be the presenting manifestation. Therefore, ophthalmologists need to be aware of this rare autoinflammatory disease.

Case Report: Self-Resolved Macular Edema Secondary to Congenital Retinal Macrovessels.

PURPOSE: To report a case of macular edema secondary to congenital retinal macrovessels (CRMs), which resolved spontaneously without any treatment. OBSERVATIONS: A 39-year-old female presented with blurry vision of the right eye for one day. Fundus examination revealed a branch of artery and vein of the inferior retinal arcade crossing the horizontal raphe. Optical coherence tomography (OCT) through the fovea showed cystoid macular edema in the outer plexiform layer. However, no leakage of the vessels was noticed by fundus fluorescein angiography (FFA). Observation was recommended with close follow-up. Two weeks later, the patient returned with good visual acuity, and the macular edema was resolved spontaneously. CONCLUSIONS: Macular edema is a possible complication of CRM by increasing retinal capillary hydrostatic pressure. Treatment is not necessary for this kind of macular edema if no leakage of the vessels is noticed on FFA.

Drug Elimination Alteration in Acute Lymphoblastic Leukemia Mediated by Renal Transporters and Glomerular Filtration.

PURPOSE: Drug elimination alteration has been well reported in acute lymphoblastic leukemia (ALL). Considering that transporters and glomerular filtration influence, to different extents, the drug disposition, and possible side effects, we evaluated the effects of ALL on major renal transporters and glomerular filtration mediated pharmacokinetic changes, as well as expression of renal drug transporters. METHODS: ALL xenograft models were established and intravenously injected with substrates of renal transporters and glomerular filtration separately in NOD/SCID mice. The plasma concentrations of substrates, after single doses, were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). RESULTS: With the development of ALL, protein expression of MDR1, OAT3 and OCT2 were increased by 2.62-fold, 1.70-fold, and 1.45-fold, respectively, whereas expression of MRP2 and MRP4 were significantly decreased by 30.98% and 45.28% in the kidney of ALL groups compared with control groups. Clearance of MDR1-mediated digoxin, OAT3-mediated furosemide, and OCT2-mediated metformin increased by 3.04-fold, 1.47-fold, and 1.26-fold, respectively. However, clearance of MRPs-mediated methotrexate was reduced by 39.5%. These results are consistent with mRNA expression. Clearance of vancomycin and amikacin, as markers of glomerular filtration rate, had a 2.14 and 1.64-fold increase in ALL mice, respectively. CONCLUSIONS: The specific alteration of renal transporters and glomerular filtration in kidneys provide a rational explanation for changes in pharmacokinetics for ALL.

Minimal surgery achieved good visual acuity in selected patients with magnetic intravitreal foreign body and traumatic cataract.

BACKGROUND: To explore minimal surgery in selected patients with intravitreal foreign body (IVFD) and traumatic cataract. METHODS: Twelve eyes of 12 patients with small ferrous IVFD and traumatic cataract without endophthalmitis, retinal injury and secondary glaucoma, between September 2015 and March 2017 were retrospectively analyzed. Primary removal of IVFD was performed by external magnetic extraction through the pars plana incision. Secondary removal of traumatic cataract by phacoemulsification and intraocular lens (IOL) implantation with or without anterior vitrectomy were performed. Patients were followed up at 1 day, 1 week, 1 month, 3 months, 6 months and 12 months after surgery. RESULTS: All patients were male with a mean age of 32 years old. All IVFDs were successfully removed without retinal injury. Two to 6 months later, the traumatic cataract was successfully removed by phacoemulsification combined with IOL implantation in the capsule bag in 10 patients. Anterior vitrectomy was implied in 2 patients with large posterior capsule rupture, and the IOLs were placed in the ciliary sulcus. Best-corrected visual acuity ranged from hand movement to 20/100 before surgery and improved ranging from 20/32 to 20/20 at the final follow-up. The IOLs were well centered. Complications such as secondary glaucoma, endophthalmitis and retinal detachment were not found. CONCLUSIONS: Primary removal of small ferrous IVFD by external magnetic extraction followed by secondary cataract removal and IOL implantation is an appropriate choice. Minimal surgery may obtain good visual outcome without complications in selected patients.

Pterygium surgery combined with the removal of a missed occult iris foreign body detected incidentally during pterygium examination: a case report.

BACKGROUND: An occult foreign body may be retained in patient with small self-sealing wound and no decreased visual acuity without complete examination. Here we report a case of a retained occult ferrous iris foreign body detected incidentally during pterygium examination. CASE PRESENTATION: A 69-year-old man presented to our ophthalmology department because of foreign body sensation and persistent redness in both eyes for 2 years. In the left eye, a pterygium, paracentral corneal opacity and a vertically oval pupil were observed. Ultrasound biomicroscopy and gonioscopy revealed a retained metallic-like foreign body partially embedded in the inferior peripheral iris. Pterygium surgery and the removal of the retained iris foreign body were performed simultaneously. No recurrent pterygium or residual foreign body was found during follow-up. CONCLUSIONS: A thorough history should be obtained and complete physical examination should be performed in patients with ocular self-sealing wounds to prevent missed intraocular foreign bodies, which may result in potential sight-threatening ocular complications.

Artisan iris-fixated intraocular lens implantation in combination with pupilloplasty-correction of aphakia with pathologically large pupil and insufficient capsular support.

OBJECTIVE: The aim of this study was to report the efficacy and safety of applying pupilloplasty in combination with Artisan iris-fixated intraocular lens (IOL) implantation in the treatment for aphakia with pathologically large pupil and insufficient capsular support. DESIGN: The study was a retrospective case series. PARTICIPANTS: Twenty-six aphakic eyes with pathologically large pupil and insufficient capsular support (from 26 patients) were included in the study. METHODS: The study patients underwent pupilloplasty in combination with Artisan iris-fixated IOL implantation. Follow-up appointments were scheduled at 1 week and at 1, 3, and 6 months postoperatively. RESULTS: The mean uncorrected visual acuity was significantly improved from logMAR 1.15 ± 0.29 to logMAR 0.37 ± 0.17, and the mean manifest refraction spherical equivalent was significantly decreased from 12.07 ± 2.20 D to -0.69 ± 0.70 D at 6 month after surgery (p < 0.05). The pupil diameter decreased significantly, from 5.7 ± 1.1 mm preoperatively to 4.5 ± 0.8 mm at 6 months after pupilloplasty (p < 0.05). Patients experienced less photophobia postoperatively. The safety parameters, including endothelial cell count, intraocular pressure, corneal astigmatism, best-corrected visual acuity, and central corneal thickness, showed no significant differences in values before and after surgery. CONCLUSIONS: The Artisan iris-fixated IOL implantation in combination with pupilloplasty can be used as an alternative way to correct aphakia with pathologically large pupil and insufficient capsular support.

The prognostic relevance of primary tumor location in patients undergoing resection for pancreatic ductal adenocarcinoma.

Different clinical presentations and prognoses have been implied between pancreatic head and body/tail cancers. We aimed to identify the prognostic relevance of primary tumor location in patients undergoing resection for pancreatic ductal adenocarcinoma (PDAC). Thirty-two pairs of patients with strictly matched early stage (II) pancreatic head and body/tail cancers were enrolled. The molecular feature of the two subtypes of PDAC was assessed on the level of miRNA expression. Out of the 64 patients, 34 (53.1%) had tumor recurrence after radical resection during the follow-up period (2.3 ± 0.8 years). Both overall and tumor-free survival were significantly higher in the patients with pancreatic body/tail cancer compared with those with pancreatic head cancer. Patient age and tumor location were the independent prognostic factors for tumor recurrence. A remarkably lower expression of miR-501-3p and higher expression of miR-375 were found and were further verified in pancreatic body/tail cancer tissues compared with pancreatic head cancer tissues. The low expression of miR-501-3p was significantly associated with a low risk of tumor recurrence. Both, subcutaneous and orthotopic PDAC mouse models presented highly invasive tumor phenotypes upon up-regulated miR-501-3p expression. An in vitro study showed that miR-501-3p promoted the invasiveness of PDAC cells possibly via suppressing E-cadherin. In summary, at resectable early stage, pancreatic body/tail cancer presents a less malignant phenotype associated with deregulation of miR-501-3p compared with pancreatic head cancer.

Idiopathic Choroidal Neovascularization: Intraocular Inflammatory Cytokines and the Effect of Intravitreal Ranibizumab Treatment.

Idiopathic choroidal neovascularization (ICNV) is a disorder that primarily affecting patients younger than 50 years and can cause severe loss of vision. Choroidal abnormalities, especially choroidal inflammation, have been thought to be involved in the pathophysiology of ICNV. However, the exact pathogenesis of ICNV remains unclear. The aim of our study was investigate the levels of 27 inflammatory cytokines in the aqueous humor of eyes with ICNV, and to determine the effect of intravitreal injection of ranibizumab (IVR) on cytokine levels. Significantly higher levels of IL-2, IL-10, IL-15, IL-17, basic FGF, and GM-CSF were observed in patients with ICNV compared with controls. However, only IL-17 levels were significantly higher in patients with ICNV compared with controls after adjusting for axial length. Furthermore, there were significant correlations between the levels of IL-10, IL-17, GM-CSF, and VEGF and the lesion area. Significant changes in visual acuity and central retinal thickness were observed after IVR. Besides VEGF, IVR also significantly reduced the levels of IL-2, IL-10, basic FGF, and IL-12, however, the IL-6 levels were significantly increased. Our results suggest that there may be an involvement of IL-17-related inflammatory processes in the etiology of ICNV.

High glucose induces mitochondrial dysfunction and apoptosis in human retinal pigment epithelium cells via promoting SOCS1 and Fas/FasL signaling.

Diabetic retinopathy (DR) is one of the most serious complications of diabetes mellitus (DM), however, the contribution of high glucose (HG) or hyperglycemia to DR is far from fully understanding. In the present study, we examined the expression of Fas/FasL signaling and suppressors of cytokine signaling (SOCS)1 and 3 in HG-induced human retinal pigment epithelium cells (ARPE-19 cells). And then we investigated the regulatory role of both Fas and SOCS1 in HG-induced mitochondrial dysfunction and apoptosis. Results demonstrated that HG with more than 40mM induced mitochondrial dysfunction via reducing mitochondrial membrane potential (MMP) and via inhibiting the Bcl-2 level, which is the upstream signaling of mitochondria in ARPE-19 cells. HG also upreuglated the Fas signaling and SOCS levels probably via promoting JAK/STAT signaling in ARPE-19 cells. Moreover, the exogenous Fas or entogenous overexpressed SOCS1 accentuated the HG-induced mitochondrial dysfunction and apoptosis, whereas the knockdown of either Fas or SOCS1 reduced the HG-induced mitochondria dysfunction and apoptosis. Thus, the present study confirmed that both Fas/FasL signaling and SOCS1 promoted the HG-induced mitochondrial dysfunction and apoptosis. These results implies the key regulatory role of Fas signaling and SOCS in DR.

Ionizing radiation-induced microRNA expression changes in cultured RGC-5 cells.

MicroRNAs (miRNAs) are a class of short non-coding RNAs that regulate gene expression at the post­transcriptional level. It has been demonstrated that miRNAs serve a crucial role in tissue development and the pathogenesis of numerous diseases. The aim of the current study was to investigate the alterations in miRNA expression in a cultured retinal ganglion cell line (RGC­5 cells) following ionizing radiation injury. Cultured RGC­5 cells were exposed to X­rays at doses of 2, 4, 6 and 8 Gy using a medical linear accelerator. Alterations in cellular morphology were observed under a phase contrast microscope and cell viability was measured using the MTT assay. Subsequent to exposure to X­ray radiation for 5 days, the viability of RGC­5 cells was significantly reduced in the 6 and 8 Gy groups, accompanied by morphological alterations. Total RNA was then extracted from RGC­5 cells and subjected to miRNA microarray analysis subsequent to exposure to 6 Gy X­ray radiation for 5 days. The results of the microarray analysis indicated that the expression levels of 12 miRNAs were significantly different between the 6 Gy and control groups, including 6 upregulated miRNAs and 6 downregulated miRNAs. To verify microarray results, a reverse transcription­quantitative polymerase chain reaction (RT­qPCR) analysis was performed. The data obtained from RT­qPCR analysis was similar to that of the the microarray analysis for alterations in the expression of the 12 miRNAs. The results of the current study indicated that miRNA expression was sensitive to ionizing radiation, which may serve an important role in mechanisms of radiation injury in retinal ganglion cells.

Endostar inhibits hypoxia-induced cell proliferation and migration via the hypoxia-inducible factor-1α/vascular endothelial growth factor pathway in vitro.

Endostar, a recombinant human endostatin, is recognized as one of the most effective angiogenesis inhibitors. The angiogenesis inhibitory effects of Endostar suggest a possible beneficial role of Endostar in choroidal neovascularization (CNV), which is predominantly induced by hypoxia. In our previous study, it was reported that Endostar may inhibit the proliferation and migration of RF/6A choroid­retinal endothelial cells. However, the inhibitory effect of Endostar on hypoxia­induced cell proliferation and migration in RF/6A cells has not yet been elucidated. Therefore, the present study investigated the effect of Endostar on hypoxia­induced cell proliferation and migration in RF/6A cells and the possible mechanisms underlying this effect. Under chemical hypoxia conditions, cell viability was increased to 114.9±10.1 and 123.6±9.6% in cells treated with 100 and 200 µm CoCl2, respectively, compared with the control (P<0.01). Pretreatment with 10­100 µg/ml Endostar significantly inhibited CoCl2­induced cell proliferation (P<0.05), and pre­treatment with 10 µg/ml Endostar for 24, 48 and 96 h attenuated CoCl2­promoted cell migration by 60.5, 48.3 and 39.6%, respectively, compared with the control (P<0.001). In addition, pretreatment with 10 µg/ml Endostar reversed the cell cycle arrest at S phase and the increased expression of hypoxia­inducible factor­1α (HIF­1α) and vascular endothelial growth factor (VEGF) mRNA in RF/6A cells treated with 200 µM CoCl2. These data indicate that Endostar inhibited CoCl2­induced hypoxic proliferation and migration, and limited cell cycle progression in vitro possibly through the HIF­1α/VEGF pathway.

Suppression of choroidal neovascularization by Endostar in rats.

Choroidal neovascularization (CNV) is common in various retinal and choroidal diseases, and may result in severe and irreversible loss of vision. Our previous studies suggested that Endostar, a novel recombinant endostatin, is able to inhibit the proliferation and migration of choroid­retinal endothelial cells. To further evaluate the effect of Endostar on the formation of CNV in vivo, a rat model of laser­induced CNV was constructed and Endostar or phosphate­buffered saline treatment was administered intravitreally every other day. Using fluorescein angiography (FA), reduced CNV incidence and leakage grade was observed in the Endostar group. In addition, CNV area and maximal thickness were prominently reduced in the Endostar group measured by choroid flat mounts and sections. Furthermore, vascular endothelial growth factor (VEGF), hypoxia­inducible factor 1α and chemokine C­X­C motif ligand 1 were markedly reduced in the Endostar group as determined by quantitative polymerase chain reaction and downregulation of VEGF was also verified by western blot analysis at the protein level. This study demonstrates that Endostar suppressed CNV in a rat model, which may be largely mediated by the downregulation of VEGF and other angiogenic molecules.

Zn-driven discovery of a hydrothermal vent fungal metabolite clavatustide C, and an experimental study of the anti-cancer mechanism of clavatustide B.

A naturally new cyclopeptide, clavatustide C, was produced as a stress metabolite in response to abiotic stress elicitation by one of the hydrothermal vent fluid components Zn in the cultured mycelia of Aspergillus clavatus C2WU, which were isolated from Xenograpsus testudinatus. X. testudinatus lives at extreme, toxic habitat around the sulphur-rich hydrothermal vents in Taiwan Kueishantao. The known compound clavatustide B was also isolated and purified. This is the first example of a new hydrothermal vent microbial secondary metabolite produced in response to abiotic Zn treatment. The structures were established by spectroscopic means. The regulation of G1-S transition in hepatocellular carcinoma cell lines by clavatustide B was observed in our previous study. The purpose of the present study was to verify these results in other types of cancer cell lines and elucidate the possible molecular mechanism for the anti-cancer activities of clavatustide B. In different human cancer cell lines, including pancreatic cancer (Panc-1), gastric cancer (MGC-803), colorectal cancer (SW-480), retinoblastoma (WERI-Rb-1) and prostate cancer (PC3), clavatustide B efficiently suppressed cell proliferations in a dose-dependent manner. Although different cancer cell lines presented variety in Max effect dose and IC50 dose, all cancer cell lines showed a lower Max effect dose and IC50 dose compared with human fibroblasts (hFB) (p < 0.05). Moreover, significant accumulations in G1 phases and a reduction in S phases (p < 0.05) were observed under clavatustide B treatment. The expression levels of 2622 genes including 39 cell cycle-associated genes in HepG2 cells were significantly altered by the treatment with 15 µg/mL clavatustide B after 48 h. CCNE2 (cyclin E2) was proved to be the key regulator of clavatustide B-induced G1-S transition blocking in several cancer cell lines by using real-time PCR.

Molecular analysis and phenotypic study in 14 Chinese families with Bietti crystalline dystrophy.

PURPOSE: To investigate the clinical features and cytochrome P450 family 4 subfamily V polypeptide 2 (CYP4V2) gene mutations in 14 Chinese families with Bietti crystalline dystrophy (BCD). METHODS: Seventeen patients from 14 unrelated Chinese families with BCD were recruited for complete clinical ophthalmic examination and genetic study. The 11 exons of CYP4V2 were amplified from genomic DNA of all patients and their family members by polymerase chain reaction (PCR) and then sequenced. Exons of TIMP3 were also sequenced in BCD patient associated with choroidal neovascularization (CNV). One hundred and seventy unrelated healthy Chinese subjects were screened for mutations in CYP4V2. RESULTS: All 17 patients with BCD had mutations in CYP4V2; one of these mutations was novel (c.219T>A, p.F73L) and four other mutations had been reported. The p.F73L mutation was a commonly detected mutation in our study (seven out of 34 alleles), either in the homozygous state or in the heterozygous state. Among the patients, considerable phenotypic variability was detected, both within and between families. Screening of TIMP3 did not find any mutation in the BCD patient associated with CNV. CONCLUSION: The novel CYP4V2 c.219T>A (p.F73L) mutation may be another recurrent mutation in Chinese patients with BCD. Our study expands the mutation spectrum of CYP4V2 and characterizes novel genotype-phenotype associations in Chinese patients with BCD.

Hypoxia-induced deregulation of miR-126 and its regulative effect on VEGF and MMP-9 expression.

OBJECTIVE: miR-126, the miRNA considered to be specially expressed in endothelial cells and hematopoietic progenitor cells, is strongly associated with angiogenesis. The purpose is to evaluate the role of miR-126 in hypoxia-induced angiogenesis and the possible mechanisms. METHODS: The expression of miR-126 was detected in hypoxia-treated RF/6A cells and diabetic retinas using real-time PCR. The miR-126 was up- or down-regulated by transfecting miR-126-mimics or inhibitors into RF/6A cells. Cell cycle analysis was performed using flow cytometry. The protein levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) were assessed by immunoblotting. RESULTS: A significantly decreased expression of miR-126 was found in hypoxia-treated RF/6A cells in a time-dependent manner compared with normoxic condition. The expression of miR-126 was also reduced in the retina tissue of streptozotocin-induced diabetic rats. The expression of VEGF and MMP-9 proteins was increased in hypoxia-induced RF/6A cells. In the functional analysis, miR-126-mimic significantly reduced the percentage of RF/6A cells in S phases compared with the negative control under hypoxic conditions. Furthermore, the VEGF and MMP-9 protein levels were sharply decreased in hypoxia-induced RF/6A cells pretreated with miR-126-mimics and increased in the cells pretreated with miR-126-inhibitors. CONCLUSIONS: miR-126 is down-regulated under hypoxic condition both in vitro and in vivo and may halt the hypoxia-induce neovascularization by suspending the cell cycle progression and inhibiting the expression of VEGF and MMP-9.

Two novel hepatocellular carcinoma cycle inhibitory cyclodepsipeptides from a hydrothermal vent crab-associated fungus Aspergillus clavatus C2WU.

Two novel cyclodepsipeptides containing an unusual anthranilic acid dimer and a D-phenyllactic acid residues, clavatustides A and B, were identified from cultured mycelia and broth of Aspergillus clavatus C2WU isolated from Xenograpsus testudinatus, which lives at extreme, toxic habitat around the sulphur-rich hydrothermal vents in Taiwan Kueishantao. This is the first example of cyclopeptides containing an anthranilic acid dimer in natural products, and the first report of microbial secondary metabolites from the hydrothermal vent crab. Clavatustides A and B suppressed the proliferation of hepatocellular carcinoma (HCC) cell lines (HepG2, SMMC-7721 and Bel-7402) in a dose-dependent manner, and induced an accumulation of HepG2 cells in G1 phase and reduction of cells in S phase.

[(-)-Epigallocatechin gallate regulates expression of apoptotic genes and protects cultured human lens epithelial cells under hyperglycemia].

(-)-Epigallocatechin gallate (EGCG), the most abundant component in green tea, has a potent anti-apoptotic activity. The purpose of this study was to investigate the protective effects of EGCG and their molecular mechanisms on high glucose-induced apoptosis of human lens epithelial cells (HLEB-3). HLEB-3 cells were exposed to various concentrations of glucose and EGCG. Cell death was assessed by MTT assay and flow cytometry using annexin V and propidium iodide. The expression of the Bcl-2 family, c-fos, c-myc and p53 was measured by real-time PCR. EGCG decreased the Bcl-2/Bax expression stimulated by a high glucose. Moreover, EGCG suppressed the high glucose-induced expression of c-fos, c-myc and p53. These findings suggest that EGCG protects HLEB-3 cells from high glucose-induced apoptosis by regulating the gene expression of the Bcl-2 family, c-fos, c-myc and p53. Thus, EGCG may have a potential protective effect against diabetic cataract formation.