Targeting acetyl-CoA carboxylase 1 for cancer therapy.

Metabolic adaptation is an emerging hallmark of tumors. De novo fatty acid synthesis is an important metabolic process to produce metabolic intermediates for energy storage, biosynthesis of membrane lipids and generation of signaling molecules. Acetyl-CoA carboxylase 1 (ACC1) is a critical enzyme in the fatty acid synthesis, which carboxylates acetyl-CoA carboxylic acid to form malonyl-CoA. The role of acetyl-CoA carboxylase 1 in fatty acid synthesis makes it a promising therapeutic target for various metabolic diseases such as non-alcoholic fatty liver disease, obesity and diabetes. Tumors have a high energy flow and a strong dependence on fatty acid synthesis. Thus, acetyl-CoA carboxylase inhibition has become a potential choice for anti-tumor therapy. In this review, we first introduced the structure and expression pattern of Acetyl-CoA carboxylase 1. We also discussed the molecular mechanisms of acetyl-CoA carboxylase 1 in the initiation and progression of various cancer types. Furthermore, acetyl-CoA carboxylase1 inhibitors has also been discussed. Collectively, we summarized the interplay between acetyl-CoA carboxylase 1 and tumorigenesis, indicating acetyl-CoA carboxylase 1 as a promising therapeutic target for tumor management.

Mechanism of piR-1245/PIWI-like protein-2 regulating Janus kinase-2/signal transducer and activator of transcription-3/vascular endothelial growth factor signaling pathway in retinal neovascularization.

Inhibiting retinal neovascularization is the optimal strategy for the treatment of retina-related diseases, but there is currently no effective treatment for retinal neovascularization. P-element-induced wimpy testis (PIWI)-interacting RNA (piRNA) is a type of small non-coding RNA implicated in a variety of diseases. In this study, we found that the expression of piR-1245 and the interacting protein PIWIL2 were remarkably increased in human retinal endothelial cells cultured in a hypoxic environment, and cell apoptosis, migration, tube formation and proliferation were remarkably enhanced in these cells. Knocking down piR-1245 inhibited the above phenomena. After intervention by a p-JAK2 activator, piR-1245 decreased the expression of hypoxia inducible factor-1α and vascular endothelial growth factor through the JAK2/STAT3 pathway. For in vivo analysis, 7-day-old newborn mice were raised in 75 ± 2% hyperoxia for 5 days and then piR-1245 in the retina was knocked down. In these mice, the number of newly formed vessels in the retina was decreased, the expressions of inflammation-related proteins were reduced, the number of apoptotic cells in the retina was decreased, the JAK2/STAT3 pathway was inhibited, and the expressions of hypoxia inducible factor-1α and vascular endothelial growth factor were decreased. Injection of the JAK2 inhibitor JAK2/TYK2-IN-1 into the vitreous cavity inhibited retinal neovascularization in mice and reduced expression of hypoxia inducible factor-1α and vascular endothelial growth factor. These findings suggest that piR-1245 activates the JAK2/STAT3 pathway, regulates the expression of hypoxia inducible factor-1α and vascular endothelial growth factor, and promotes retinal neovascularization. Therefore, piR-1245 may be a new therapeutic target for retinal neovascularization.

Maternally expressed gene 3 regulates retinal neovascularization in retinopathy of prematurity.

The mouse model of oxygen induced retinopathy is suitable for the study of various retinal neovascularization diseases, including retinopathy of prematurity. The maternally expressed gene 3 (MEG3) has been demonstrated to have an inhibitory effect on diabetic retinopathy. In this study, we investigated the role of MEG3 overexpression in oxygen-induced retinopathy in mice. The results showed that MEG3 overexpression effectively inhibited the production of retinal neovascularization in oxygen-induced retinopathy mice. It acts by down-regulating the expression of phosphoinositide 3-kinase, serine/threonine kinase, and vascular endothelial growth factor and pro-inflammatory factors. MEG3 overexpression lentivirus has a future as a new method for the clinical treatment of retinopathy of prematurity. The animal experiments were approved by the Animal Ethics Committee of Shengjing Hospital of China Medical University, China (approval No. 2016PS074K) on February 25, 2016.

Effects of long non-coding RNA myocardial infarction-associated transcript on retinal neovascularization in a newborn mouse model of oxygen-induced retinopathy.

Whether long non-coding RNA myocardial infarction-associated transcript is involved in oxygen-induced retinopathy remains poorly understood. To validate this hypothesis, we established a newborn mouse model of oxygen-induced retinopathy by feeding in an oxygen concentration of 75 ± 2% from postnatal day 8 to postnatal day 12, followed by in normal air. On postnatal day 11, the mice were injected with the myocardial infarction-associated transcript siRNA plasmid via the vitreous cavity to knockdown long non-coding RNA myocardial infarction-associated transcript. Myocardial infarction-associated transcript siRNA transcription significantly inhibited myocardial infarction-associated transcript mRNA expression, reduced the phosphatidylinosital-3-kinase, phosphorylated Akt and vascular endothelial growth factor immunopositivities, protein and mRNA expression, and alleviated the pathological damage to the retina of oxygen-induced retinopathy mouse models. These findings suggest that myocardial infarction-associated transcript is likely involved in the retinal neovascularization in retinopathy of prematurity and that inhibition of myocardial infarction-associated transcript can downregulate phosphatidylinosital-3-kinase, phosphorylated Akt and vascular endothelial growth factor expression levels and inhibit neovascularization. This study was approved by the Animal Ethics Committee of Shengjing Hospital of China Medical University, China (approval No. 2016PS074K) on February 25, 2016.

Matrix metalloproteinase-9 and vascular endothelial growth factor expression change in experimental retinal neovascularization.

AIM: To investigate the signal transduction mechanism of matrix metalloproteinase-9 (MMP-9) mediated- vascular endothelial growth factor (VEGF) expression and retinal neovascularization (RNV) in oxygen-induced retinopathy (OIR) model. METHODS: C57BL/6J mice were divided into four groups: control group, OIR group, OIR control group (phosphate-buffered saline by intravitreal injection) and treated group [tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) by intravitreal injection]. OIR model was established in C57BL/6J mice exposed to 75%±2% oxygen for 5d. mRNA level and protein expression of MMP-9, TIMP-1 and VEGF were measured by real-time polymerase chain reaction and Western blotting, and located by immunohistochemistry. RESULTS: Levels of MMP-9 and VEGF in retina were significantly increased in animals with OIR and OIR control group. Levels of TIMP-1 in retina was significantly reduced in animals with OIR and OIR control group. Furthermore, a significant correlation was found between MMP-9 and VEGF. Intravitreal injection of TIMP-1 significantly reduced MMP-9 and VEGF expression of the OIR mouse model (all P<0.05). CONCLUSION: These results demonstrate that MMP-9-mediated up-regulation of VEGF promotes RNV in retinopathy of prematurity (ROP). TIMP-1 may be a potential target for the prevention and treatment of ROP.

CCN1/Cyr61-PI3K/AKT signaling promotes retinal neovascularization in oxygen-induced retinopathy.

Retinal neovascularization (RNV) is a characteristic pathological finding of retinopathy of prematurity (ROP). Cysteine-rich 61 [Cyr61, also known as CCN family member 1 (CCN1)] has been reported to mediate angiogenesis. The aim of the present study was to investigate the mechanisms of CCN1/Cyr61-phosphoinositide 3-kinase (PI3K)/AKT signaling in ROP. The contribution of CCN1 to human umbilical vein endothelial cell (HUVEC) proliferation and apoptosis under hypoxic conditions was determined using a cell counting kit­8 (CCK-8) and Annexin V/propidium iodide (PI) staining, respectively, as well as using siRNA targeting CCN1 (CCN1 siRNA). The cells exposed to hypoxia were also treated with the PI3K/AKT inhibitor, LY294002. In addition, mouse pups with oxygen-induced retinopathy (OIR) were administered an intravitreal injection of CCN1 siRNA. RNV was assessed by magnesium-activated adenosine diphosphate-ase (ADPase) staining. RT-qPCR, western blot analysis, immunofluorescence staining and immunohistochemistry were used to detect the distribution and expression of CCN1, PI3K and AKT. Exposure to hypoxia increased the neovascularization clock hour scores (from 1.23±0.49 to 5.60±0.73, P<0.05) and the number of preretinal neovascular cells, as well as the mRNA and protein expression levels of CCN1, PI3K and AKT (all P<0.05). The injection of CCN1 siRNA decreased the neovascularization clock hour scores and the number of preretinal neovascular cells (1.53±0.72 vs. 4.76±1.04; 12.0±2.8 vs. 31.4±2.6, respectively, both P<0.05), as well as the mRNA and protein expression levels of CCN1, PI3K and AKT (protein, -45.3, -22.5 and -28.4%; mRNA, -43.7, -58.7 and -42.9%, respectively, all P<0.05) compared to the administration of scrambled siRNA under hypoxic conditions. Treatment with LY294002 decreased the mRNA and protein expression levels of CCN1 in the cells exposed to hypoxia (both P<0.05). The administration of CCN1 siRNA resulted in less severe neovascularization in the eyes of the the mouse pups with OIR. Thus, out data suggest that CCN1 plays an important role in RNV in ROP, and may thus be a potential target for the prevention and treatment of ROP.

[The results and analysis of making corneal flaps with Moria M(2) microkeratome in LASIK].

OBJECTIVE: To investigate the results and technology of making corneal flaps with Moria M(2) microkeratome. METHODS: Eight hundred and six corneal flaps (in 409 cases) were made using Moria M(2) microkeratome in LASIK. The group consisted of 205 males (405 eyes), whose mean age was (23.61 +/- 5.44) years, mean refractive spherical equivalent was (-6.32 +/- 3.61) D, and mean corneal thickness was (542.72 +/- 29.54) micro m. The 130-micron head option was chosen, the pressure was less than 250 mm Hg (1 mm Hg = 0.133 kPa), the stop-ring was adjusted to the 8.0 mm position and the suction ring was chosen according to corneal curvatures. RESULTS: All 806 corneal flaps were made successfully at one time with suitable hinge size, and without ruptured or thin or incomplete flaps. Flaps could be turned and reattached easily. There was no breaking down during the surgical procedure. The flaps showed smooth edges with smooth keratectomy beds. COMPLICATIONS: (1) Free flaps occurred in 3 eyes (0.37%). (2) Island phenomenon occurred in 2 eyes (0.25%). (3) Failure to make the flaps occurred in 3 eyes (0.37%). CONCLUSION: All 806 corneal flaps were made successfully at one time with no serious complications. Choosing the suction ring according to corneal curvature, checking blades preoperatively and inserting blades correctly may help to avoid complications when making corneal flaps with Moria M(2) microkeratome.

Clinical effect of improved viscocanalostomy for the treatment of primary congenital glaucoma.

AIM: To evaluate the clinical effect of improved viscocanalostomy in patients with primary congenital glaucoma. METHODS: Retrospective analysis of improved viscocanalostomy was performed on 51 eyes of 42 patients with primary congenital glaucoma. The outcome evaluation included postoperative intraocular pressure(IOP), corneal diameter, cup/disc ratio and complications. All patients were followed up at week 1, month 1, 3, 6 and 12. RESULTS: The results revealed that postoperative IOP was decreased from (38.57±13.61)mmHg to (10.53±3.91)mmHg, (14.89±5.26)mmHg, (15.42±5.11)mmHg, (13.82±3.46)mmHg, (13.16±5.29)mmHg at follow-up time of 1 week, 1, 3, 6, 12 months (P<0.001). The postoperative corneal diameter was decreased significantly (P=0.002); The mean cup/dish ratio wasn't significantly different (P=0.148) before and after the surgery, the cup/dish ratio of successful surgery was evidently decreased (preoperative 0.7±0.2, postoperative 0.6±0.3, P=0.007), but the complications like as unformed anterior chamber were not observed. The mean follow-up period was 12 months. CONCLUSION: Improved viscocanalostomy improves the clinical effects of the patients with primary congenital glaucoma, such as higher success rates, lower postoperative mean IOP and fewer complications.

Influence of geranylgeranylacetone on the expression of HSP70 in retina of rats with chronic IOP elevation.

AIM: To study the effects of geranylgeranylacetone (GGA) on the expression of heat shock protein70 (HSP70) on retinal ganglion cells (RGC) in rats with chronic intraocular pressure (IOP) elevation. METHODS: Seventy Wistars were divided into blank control group (10 rats), chronic hypertension group (30 rats) and GGA group (30 rats). Chronic hypertension was created by cauterizing the superficial scleral veins. 800mg/kg/d GGA was given by oral daily after cauterization. Immunohistochemistry was used respectively to observe the changes of expression of HSP70 in the model rats and GGA interference rats at different time points during the course of chronic IOP elevation. RESULTS: The successful model was identified as the IOP over 40% of normal rats. The retinal thickness was significantly reduced in model group and model+GGA group compared with normal rats from 21 days through 28 days after cauterization (P<0.05), and that of model rats was obviously decreased in comparison with model+GGA rats (P<0.05). The number of ganglion cells was significantly decreased in model rats and model+GGA rats compared with normal rats from 21 days and 28 days. The stronger expression intensity (IOD) value was seen for HSP70 in the model+GGA rats by immunochemistry (P<0.01). CONCLUSION: Systemic administration of GGA protects retina from chronic IOP elevation by regulating the expression of HSP70.

Expression of Nogo-A on the retina in rat model with chronic ocular hypertension.

AIM: To study the expressive variation of Nogo-A on rat retina in the process of chronic ocular hypertension. METHODS: Thirty-six healthy adult male Wistars were randomly divided into control group (6 rats) and chronic hypertension group (30 rats). Chronic hypertension was created by cauterizing the superficial scleral veins. Immunohistochemistry technique was used to evaluate the expressive varieties of Nogo-A at different time points during the course of chronic ocular hypertension. RESULTS: The success of the model was indicated by over 40% of increase in the IOP as compared with normal rats. Compared with control group, as time passed chronic hypertension group gradually had detectable morphology changes in the retina. At the 21st day of chronic ocular hypertension, retinas became thinner and the quantity of retinal ganglion cells (RGC) decreased (P<0.05). Assoicated with the morphological changes, the expression of Nogo-A was strongly increased (P<0.05). CONCLUSION: Myelin associated protein Nogo-A plays a part in the process of chronic ocular hypertension.

Efficacy and tolerability of one-site versus two-site phacotrabeculectomy: a meta-analysis.

AIM: To evaluate the efficacy and tolerability of one-site versus two-site phacotrabeculectomy in the treatment of patients with coexisting cataract and glaucoma. METHODS: A comprehensive literature meta-analysis was performed according to the Cochrane Collaboration methodology to identify controlled clinical trials comparing one-site with two-site phacotrabeculectomy. The studies meeting the predefined criteria were reviewed systematically by meta-analysis. Efficacy estimates were measured by standardised mean difference (SMD) for the percentage intraocular pressure (IOP) reduction from baseline to end point, odds ratio (OR) for the percentage having a best-corrected visual acuity (BCVA) of 0.5 or better after surgery and relative risk (RR) for complete success rates. Tolerability estimates were measured by RR for adverse events. All of outcomes were reported with 95% confidence interval (CI). Data were synthesised by Stata 10.1 for Windows. RESULTS: Two-site phacotrabeculectomy was associated with numerically greater, and significant efficacy than one-site in lowering IOP (SMD, -0.19; 95% CI, -0.33 to -0.04; P=0.01). Numerically greater, but nonsignificant proportions of two-site patients than one-site patients had a BCVA of 0.5 or better (OR, 0.65; 95% CI, 0.30 to 1.39; P=0.26).Numerically greater, but nonsignificant proportions of two-site patients than one-site patients achieved the target IOP without anti-glaucoma medication at the end point (RR, 0.94; 95% CI, 0.84 to 1.04; P=0.22). Furthermore, there was nonsignificant difference in adverse events between two surgical procedures. CONCLUSION: The efficacy of two-site phacotrabeculectomy appears to be superior to one-site phacotrabeculectomy. One-site and two-site phacotrabeculectomy are similarly tolerable in postoperative adverse events.

Efficacy and tolerability of one-site versus two-site phaco-trabeculectomy: a meta-analysis of randomized controlled clinical trials.

BACKGROUND: Phacotrabeculectomy can be performed using one-site or two-site incisions. This meta-analysis evaluated the efficacy and tolerability of one-site versus two-site phacotrabeculectomy in the treatment of patients with coexisting cataract and glaucoma. METHODS: A comprehensive literature search was performed according to the Cochrane Collaboration methodology to identify randomized controlled clinical trials comparing one-site with two-site phacotrabeculectomy. Studies meeting our predefined criteria were included in the meta-analysis. Efficacy estimates were measured by weighted mean difference (WMD) for the percentage intraocular pressure (IOP) reduction from baseline to end point, relative risk (RR) for the proportion of patients with a best-corrected visual acuity (BCVA) of 0.5 or better after surgery and complete success rates. Tolerability estimates were measured by RR for adverse events. All of outcomes were reported with 95% confidence interval (95%CI). Data were synthesised by Stata 10.1 for Windows. RESULTS: Two-site phacotrabeculectomy was associated with greater reductions in IOP than the one-site procedure (WMD: -5.99, 95%CI: -10.74 - -1.24, P = 0.01). A greater proportion of patients also achieved a BCVA of 0.5 or better (RR: 0.91, 95%CI: 0.74 - 1.12, P = 0.36) and the target IOP without anti-glaucoma medication at the study end point (RR: 0.94, 95%CI: 0.83 - 1.07, P = 0.34) after two-site than one-site phacotrabeculectomy, but the differences were not significant. There were no significant differences in adverse events between two surgical procedures. CONCLUSIONS: Two-site phacotrabeculectomy is superior to one-site phacotrabeculectomy in reducing IOP, but other post-operative effects are similar. One-site and two-site phacotrabeculectomies have similar adverse event rates.

The role of CTGF in the diabetic rat retina and its relationship with VEGF and TGF-ß(2) , elucidated by treatment with CTGFsiRNA.

PURPOSE: The critical association of connective tissue growth factor (CTGF) with diabetic retinopathy (DR) remains to be clarified. We detected alterations in the gene and protein expression of CTGF and related cytokines, including vascular endothelial growth factor (VEGF) and transforming growth factor-ß(2) (TGF-ß(2) ), and their response to small interfering RNA (siRNA) targeting the CTGF (CTGFsiRNA) in the retina of diabetic rats. The relationships between CTGF, VEGF and TGF-ß(2) levels, as well as the degree of apoptosis in the diabetic retina, were also investigated. METHODS: Diabetes was induced in rats by the ß-cell toxin streptozotocin (STZ). Retinas were obtained from control and diabetic rats and similar animals treated with CTGFsiRNA by intravitreal injection. mRNA level and protein expression of CTGF, VEGF and TGF-ß(2) were measured by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting, and located by immunohistochemistry. Retinal apoptosis was detected by TUNEL staining. RESULTS: The levels of CTGF, VEGF and TGF-ß(2) and the number of TUNEL-positive nuclei were significantly higher in diabetic retinas than in control retinas (p<0.01). The level of CTGF rose at 8weeks, earlier than levels of VEGF and TGF-ß(2) , which rose at 12weeks after the onset of diabetes. The difference was significant (p<0.05). siRNA-mediated inhibition of CTGF mRNA inhibited retinal VEGF and TGF-ß(2) and also resulted in a significant decrease in apoptosis. Significant correlations were found between CTGF and VEGF (p=0.009), CTGF and TGF-ß(2) (p=0.01), and apoptosis and these three cytokines (p<0.01) in the rat retina early in diabetes. CONCLUSIONS: These results suggest that the diabetes-mediated increase in CTGF upregulates VEGF and TGF-ß(2) expression and induces apoptosis in the retina. This elevation may be inhibited by treatment with CTGFsiRNA. Connective tissue growth factor may serve as a potential target for the prevention and treatment of DR.