Novel CCR3-targeted cyclic peptides as potential therapeutic agents for age-related macular degeneration via inhibiting angiogenesis and reducing retinal photoreceptor damage.

The prolonged intravitreal administration of anti-vascular endothelial growth factor (VEGF) drugs is prone to inducing aberrant retinal vascular development and causing damage to retinal neurons. Hence, we have taken an alternative approach by designing and synthesizing a series of cyclic peptides targeting CC motif chemokine receptor 3 (CCR3). Based on the binding mode of the N-terminal region in CCR3 protein to CCL11, we used computer-aided identification of key amino acid sequence, conformational restriction through different cyclization methods, designed and synthesized a series of target cyclic peptides, and screened the preferred compound IB-2 through affinity. IB-2 exhibits excellent anti-angiogenic activity in HRECs. The apoptosis level of 661W cells demonstrated a significant decrease with the escalating concentration of IB-2. This suggests that IB-2 may have a protective effect on photoreceptor cells. In vivo experiments have shown that IB-2 significantly reduces retinal vascular leakage and choroidal neovascularization (CNV) area in a laser-induced mouse model of CNV. These findings indicate the potential of IB-2 as a safe and effective therapeutic agent for AMD, warranting further development.

Angiogenic and Fibrogenic Dual-effect of Gremlin1 on Proliferative Diabetic Retinopathy.

Ocular angiogenic diseases, such as proliferative diabetic retinopathy (PDR), are often characterized by pathological new vessels and fibrosis formation. Anti-vascular endothelial growth factor (VEGF) therapy, despite of its efficiency to inhibit new vessels, has limitations, including drug resistance and retinal fibrosis. Here, we identified that Gremlin1, a novel angiogenesis and fibrosis inducer, was secreted from Müller glial cells, and its expression increased in the vitreous fluid from patients with PDR. Mechanistically, Gremlin1 triggered angiogenesis by promoting endothelial-mesenchymal transition via the EGFR/RhoA/ROCK pathway. In addition, Gremlin1 activated microglia to present profibrotic and fibrogenic properties. Further, anti-Gremlin1 antibody inhibited ocular angiogenesis and microglia fibrosis in mouse models. Collectively, Gremlin1 could be a potential therapeutic target in the treatment of ocular angiogenic diseases.

Intra-abdominal infection after tumor surgery: tigecycline combined with ß-lactam antibiotics versus tigecycline alone.

BACKGROUNDS: Tigecycline has a broad spectrum of antimicrobial activity and has been approved for the treatment of complicated intra-abdominal infections. However, it is debatable whether tigecycline should be used alone or in combination. This study aimed to investigate whether tigecycline plus ß-lactam antibiotics (combination therapy [CT] group) are superior to tigecycline alone (monotherapy [MT] group) in non-critically ill intra-abdominal infection patients after tumor surgery. METHODS: This was a multicenter, retrospective cohort study. The primary outcome was mortality during the hospital stay. Secondary outcomes were clinical success rate, microbial eradication rate, relapse rate within one week, course of treatment, and adverse effects. Propensity score matching (PSM) was used to adjust the degree of infection before medication between the MT and CT groups. Univariate comparisons were performed using the chi-squared test for qualitative variables and Student's t-test or the Mann-Whitney U-test for continuous variables, as appropriate. Multivariate logistic regression analysis was performed to examine the relationship between antimicrobial treatments and mortality during hospitalization. The paired samples Wilcoxon test was used to compare the parameters before and after medication. RESULTS: In total, 291 patients were included in the final analysis: 128 in MT group and 163 in CT group. Mortality rate was 6.25% in the MT group and 6.13% in the CT group (P = 0.97). Multivariate logistic regression model showed that carbapenem-resistant organisms (OR: 4.35, 95% CI: 2.36 ~ 61.70) and age > 65 (OR: 1.32, 95% CI:1.19 ~ 3.01) were independent risk factors for death. CT group had a shorter defervescence time (P < 0.05), with less likelihood of relapse (P < 0.05) but had a more significant effect on activated partial thromboplastin and prothrombin time. CONCLUSIONS: Tigecycline plus ß-lactam wasn't superior to tigecycline monotherapy for the treatment of non-critically ill patients with intra-abdominal infection. But for advanced age patients with cancer, tigecycline combination therapy maybe a better choice in terms of mortality.

JP1, a polypeptide specifically targeting integrin αVß3, ameliorates choroidal neovascularization and diabetic retinopathy in mice.

Anti-vascular endothelial growth factor (VEGF) drugs have revolutionized the treatment of neovascular eye diseases, but responses are incomplete in some patients. Recent evidence shows that integrins are involved in the pathogenesis of neovascular age-related macular degeneration and diabetic retinopathy. JP1, derived from an optimized seven-amino-acid fragment of JWA protein, is a polypeptide specifically targeting integrin αVß3. In this study we evaluated the efficacy of JP1 on laser-induced choroidal neovascularization (CNV) and retinal vascular leakage. CNV mice received a single intravitreal (IVT) injection of JP1 (10, 20, 40 µg) or ranibizumab (RBZ, 10 µg). We showed that JP1 injection dose-dependently inhibited laser-induced CNV; the effect of RBZ was comparable to that of 20 µg JP1; a combined IVT injection of JP1 (20 µg) and RBZ (5 µg) exerted a synergistic effect on CNV. In the 3rd month after streptozotocin injection, diabetic mice receiving IVT injection of JP1 (40 µg) or RBZ (10 µg) once a week for 4 weeks showed significantly suppressed retinal vascular leakage. In both in vivo and in vitro experiments, JP1 counteracted oxidative stress and inflammation via inhibiting ROS/NF-κB signaling in microglial cells, and angiogenesis via modulating MEK1/2-SP1-integrin αVß3 and TRIM25-SP1-MMP2 axes in vascular endothelial cells. In addition, intraperitoneal injection of JP1 (1, 5 or 10 mg) once every other day for 3 times also dose-dependently inhibited CNV. After intraperitoneal injection of FITC-labeled JP1 (FITC-JP1) or FITC in laser-induced CNV mice, the fluorescence intensity in the CNV lesion was markedly increased in FITC-JP1 group, compared with that in FITC group, confirming that JP1 could penetrate the blood-retinal barrier to target CNV lesion. We conclude that JP1 can be used to design novel CNV-targeting therapeutic agents that may replace current invasive intraocular injections.

Anti-Vascular Endothelial Growth Factor Drug Conbercept-Loaded Peptide Hydrogel Reduced Angiogenesis in the Neovascular Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) accounts for 8.7% of the global blindness and neovascular form of AMD (nAMD) occupies a large proportion of severe visual loss and legal blindness caused by AMD with a relatively low incidence rate. Choroidal neovascularization (CNV) is overwhelmingly responsible for the occurrence of nAMD as bleeding and fluid leakage followed by abnormal formation of blood vessels could directly lead to loss of central vision so that reduce the choroidal angiogenesis is an ideal treatment method of nAMD. VEGF is an important cytokine which promote the signaling pathway of angiogenesis and the abnormal expression of VEGF is verified in great many CNV cases. Several anti-VEGF drugs have been widely used in clinical treatments such as ranibizumab, bevacizumab and aflibercept. Conbercept, as an originally developed drug in China, has attracted great attention. For the purpose of better treatment efficacy, our group designed a short chain peptide (Sequence: DDIIIRH-NH2, M.W.880.99) for controlled drug release to remedy the drawback of the short half-time period. The peptide could self-assembled into a stable 'hydrogel under pH 7.4 condition and the 3D structure was clearly observed in TEM study. Rheological study exhibited its great injectability so that the hydrogel was a material for intravitreal injection. Statistics exhibited that the hydrogel could release approximately 50% of total conbercept. The In vitro experiments showed that either dose-dependent or the time-dependent incubation with peptide would not decrease the cell viability of HREC, revealing that the peptide was biocompatible. The most important is that co-incubation with HREC obviously reduced the HREC proliferation and tube formation induced by VEGF, ensuring its potential for the treatment efficacy of nAMD.