LncRNA Meg3 knockdown reduces corneal neovascularization and VEGF-induced vascular endothelial angiogenesis via SDF-1/CXCR4 and Smad2/3 pathway.

The crucial effect of vascular endothelial growth factor (VEGF)-induced vascular angiogenesis has been well known in corneal neovascularization (CNV). This research aimed to determine the underlying value and mechanism of Meg3 on CNV in vivo and in vitro. In an alkali-burned mouse model, length and area of new vessels were increased along with thinning of corneal epithelium, accompanied by the overexpression of Meg3. Notably, subconjunctival injection of shMeg3 suppressed the degree of injury in cornea, causing expression of the angiogenesis markers--VEGF-A and CD31 decreased. In VEGF-induced human umbilical vein endothelial cells (HUVECs), knockdown of Meg3 antagonized the enhancement of viability, proliferation, wound healing ability and angiogenesis by VEGF. The proteins expression of VEGF-A, CD31, SDF-1/CXCR4 as well as phosphoraylation-Smad2/3 pathways, which were related to angiogenesis, were reduced with Meg3 deficiency. Overall, knockdown of Meg3 alleviated formation of neovascularization in alkali-burned corneas and reduced VEGF-induced angiogenesis by inhibiting SDF-1/CXCR4 and Smad2/3 signaling in vitro.

Vascular endothelial growth factor-loaded poly-lactic-co-glycolic acid nanoparticles with controlled release protect the dopaminergic neurons in Parkinson's rats.

Vascular endothelial growth factor (VEGF) had neuroprotective effects on dopaminergic (DA) neurons. In order to overcome the gastrointestinal digestion and bioaccessibility, VEGF was encapsulated with poly-lactic-co-glycolic acid nanospheres (NS) in order to prevent the VEGF degradation until its release. The caudal administration of VEGF and NS encapsulated VEGF at different doses (1.0, 10.0, and 100.0 ng/ml) on the rats with Parkinson's disease lesion was evaluated. Intravenous injected VEGF at the dose of 1 ng/ml displayed the strongest neuroprotective effect than other groups as well as the stereotaxic group. The NS encapsulated with VEGF can pass through blood-brain barrier and protect the DA neurons. There was no significant difference between intravenous injection method and stereotaxic method, while the first method is simpler and convenient. Injection of NS encapsulated with VEGF may become a valuable neurorescuing therapeutic approach for Parkinson's disease.

Pegaptanib: new drug. In macular degeneration: too many risks for too little benefit.

(1) Age-related macular degeneration with vascular proliferation can markedly hamper vision. In patients with subfoveolar involvement, verteporfin photodynamic therapy slows the loss of visual acuity on the EDTRS scale in about 15% of patients after 2 years of follow-up. (2) Pegaptanib, a vascular endothelial growth factor (VEGF) inhibitor, has been approved for the treatment of the neovascular form of age-related macular degeneration. (3) Two double-blind placebo-controlled trials involved a total of 1208 patients. When pegaptanib was injected into the eye every 6 weeks, at a dose of 0.3 mg, visual loss measured one year after beginning treatment was slowed in about 15% more patients on pegaptanib than on placebo. Efficacy during the second year is uncertain. Pegaptanib has not been compared with other treatments, nor has it been assessed in combination with verteporfin. (4) A variety of ocular adverse events were reported during clinical trials, three of which were serious and each affected about 1% of patients: endophthalmia, retinal detachment, and cataracts. Transient ocular hypertension occurred in about 15% of patients. A few cases of retinal arterial and venous thrombosis have been described. No long-term adverse effects were reported after clinical trials, but hypersensitivity reactions were reported post-approval. (5) Treatment with pegaptanib involves an intraocular injection every 6 weeks under local anaesthesia and under conditions of surgical asepsis. (6) In practice, an indirect comparison suggests that intraocular pegaptanib is no more effective than verteporfin photodynamic therapy. In contrast, adverse events are more numerous and treatment is less convenient.

Pathophysiology of cardiotoxicity from target therapy and angiogenesis inhibitors.

The progress in cancer therapy and the increase in number of long-term survivors reveal the issue of cardiovascular side-effects of anticancer drugs. Cardiotoxicity has become a significant problem, and the risks of adverse cardiac events induced by systemic drugs need to be seriously considered. Potential cardiovascular toxicities linked to anticancer agents include arrhythmias, myocardial ischemia and infarction, hypertension, thromboembolism, left ventricular dysfunction, and heart failure. It has been shown that several anticancer drugs seriously affect the cardiovascular system, such as ErbB2 inhibitors, vascular endothelial growth factor (VEGF) inhibitors, multitargeted kinase inhibitors, Abelson murine leukemia viral oncogene homolog inhibitors, and others. Each of these agents has a different mechanism through which it affects the cardiovascular system. ErbB2 inhibitors block the ErbB4/ErbB2 heterodimerization pathway triggered by Neuregulin-1, which is essential for cardiomyocyte survival. VEGF signaling is crucial for vascular growth, but it also has a major impact on myocardial function, and the VEGF pathway is also essential for maintenance of cardiovascular homeostasis. Drugs that inhibit the VEGF signaling pathway lead to a net reduction in capillary density and loss of contractile function. Here, we review the mechanisms and pathophysiology of the most significant cardiotoxic effects of ErbB2 inhibitors and antiangiogenic drugs. Moreover, we highlight the role of cardioncology in recognizing these toxicities, developing strategies to prevent or minimize cardiovascular toxicity, and reducing long-term cardiotoxic effects.

Emerging therapeutic targets in psoriasis.

Biopharmaceuticals that target specific disease-mediating molecules have advanced our understanding of the pathogenesis of psoriasis. The traditional paradigm that psoriasis is primarily a disease of epidermal cells has been replaced with a model that now includes keratinocyte-derived factors, inflammatory mediators and angiogenic mechanisms. Recent studies have highlighted some of the key molecules involved in all of these pathogenic processes. Several have already been evaluated as putative targets in in vitro and in vivo studies, whereas other molecules are significantly upregulated in psoriasis and require further study to elucidate their role and contribution to disease. Although not all these molecules will eventually qualify as drug targets, data from similar experimental strategies are predicted to underpin the next generation of candidate targets and novel therapeutic approaches.

A novel bispecific immunotoxin delivered by human bone marrow-derived mesenchymal stem cells to target blood vessels and vasculogenic mimicry of malignant gliomas.

BACKGROUND: In previous years, immunotoxins have been shown to be a greatly promising therapeutic tool for brain malignancies, such as gliomas. Human mesenchymal stem cells (hMSCs) exhibit tropism to tumor tissue. However, the effect of bispecific immunotoxins in malignant gliomas is still unknown. The aim of this study was to investigate the function of bispecific immunotoxins in human malignant gliomas. MATERIALS AND METHODS: In the present study, the bispecific immunotoxin VEGF165-ephrin A1-PE38KDEL was established using deoxyribonucleic acid shuffling and cloning techniques. The VEGF165-ephrin A1-PE38KDEL was delivered by hMSCs to mouse malignant gliomas. The effects of the bispecific immunotoxins on glioma-derived blood vessels and vasculogenic mimicry to elucidate the molecular mechanisms underlying the antitumorigenic effects of immunotoxins were examined in vivo. RESULTS: In vitro, transfected hMSCs significantly inhibited the cell viability of gliomas cell lines U87 and U251 in a dose-dependent manner compared with untransfected hMSCs (P<0.01). In vivo, the intratumoral injection of engineered hMSCs was effective at inhibiting tumor growth in a malignant glioma tumor model. CONCLUSION: The bispecific immunotoxin secreted from hMSCs acts as a novel strategy for improving treatment options for malignant gliomas in the clinic.