Potent Anti-angiogenic Effects Research Articles

Preparation, Characterization, DFT Calculations, biological evaluations and Molecular docking studies of benzimidazolium-based n-heterocyclic carbenes and selenium-adducts

This study involves designing through DFT, synthesis, and characterization of three benzimidazolium salts (AL1-AL3) and their corresponding selenium adducts (AC1-AC3). The compounds were characterized theoretically as well as experimentally through FT-IR and 1H &13C NMR. Theoretical calculations were performed using the B3LYP/6–31 G (d, p) levels of theory to determine various optical and chemical properties of the designed molecules. The HOMO/LUMO energies and their energy gaps were also calculated to assess the structure–activity relationships. In vitro testing against the Human breast Adenocarcinoma cell line (MCF-7) was conducted using the MTT assay and 5-Fluorouracil (standard) was used for the comparison of results. The ligand AL3 showed maximum inhibitory potential (66.51 ± 0.82) even approaching the standard 5FU while the complex AC3 showed maximum viability with the least inhibition value as (21.7 ± 0.73) against MCF7 cell line. The antioxidant potential for scavenging DPPH radicals was also assessed, revealing that AL1 has the greatest potential, with a value of 62.01 ± 0.9. The interactions of the complexes with various proteins were also assessed via molecular docking studies, revealing strong binding energies and ligand affinities towards angiogenic factors such as VEGF-A, EGF, HIF, and COX-1. This suggests that the anticancer activities of the complexes AC1-AC3 may be attributed to their potent anti-angiogenic effects. Moreover, selenium-NHC adducts exhibited more significant anticancer potential as compared to their ligands. Furthermore, the antibacterial and antifungal potential of compounds AC1-AC3 was assessed. Notably, the ligand AL2 exhibited significant antibacterial activity against E. coli, as evidenced by a zone of inhibition (ZI) value of 17.5 ± 0.29 mm, whereas AL3 demonstrated the highest activity against P. multocida showing the ZOI value of 18.5 ± 0.38. Among all the synthesized compounds, AL1 displayed the most significant antifungal activity against F. avenaceum (27 ± 0.51 mm), surpassing even the standard drug gentamycin (13 ± 0.23 mm), which was tested under the same conditions. However, its corresponding Se-NHC, AC1, adduct was found to be inactive. Overall, AL3 and its corresponding Se-NHC adduct (AC3), demonstrated superior biological potential against the majority of the tested strains.

Enhanced anti-angiogenic effects of aprepitant-loaded nanoparticles in human umbilical vein endothelial cells

Recent advancements in cancer therapy have led to the development of novel nanoparticle-based drug delivery systems aimed at enhancing the efficacy of chemotherapeutic agents. This study focuses on evaluating aprepitant-loaded PLGA and Eudragit RS 100 nanoparticles for their potential antiangiogenic effects. Characterization studies revealed that aprepitant-loaded nanoparticles exhibited particle sizes ranging from 208.50 to 238.67 nm, with monodisperse distributions (PDI < 0.7) and stable zeta potentials (between − 5.0 and − 15.0 mV). Encapsulation efficiencies exceeding 99% were achieved, highlighting the efficacy of PLGA and Eudragit RS 100 as carriers for aprepitant. Cellular uptake studies demonstrated enhanced internalization of aprepitant-loaded nanoparticles by HUVEC cells compared to free aprepitant, as confirmed by fluorescence microscopy. Furthermore, cytotoxicity assays revealed significant dose-dependent effects of aprepitant-loaded nanoparticles on HUVEC cell viability, with IC50 values at 24 h of 11.9 µg/mL for Eudragit RS 100 and 94.3 µg/mL for PLGA formulations. Importantly, these nanoparticles effectively inhibited HUVEC cell migration and invasion induced by M2c supernatant, as evidenced by real-time cell analysis and gene expression studies. Moreover, aprepitant-loaded nanoparticles downregulated VEGFA and VEGFB gene expressions and reduced VEGFR-2 protein levels in HUVEC cells, highlighting their potential as antiangiogenic agents. Overall, this research underscores the promise of nanoparticle-based aprepitant formulations in targeted cancer therapy, offering enhanced therapeutic outcomes through improved drug delivery and efficacy against angiogenesis.

Core-shell structured nanomembrane with sequential immune and vascular isolation effects followed by chondrogenic induction to promote stable stem cell-based subcutaneous cartilage regeneration in large animals

Bone marrow stem cell (BMSC)-regenerated cartilage (BRC) shows promising prospects for clinically repairing cartilage defects. However, when subcutaneously implanted into immunocompetent large animals, BRC is prone to ossification due to vascular invasion and inflammatory infiltration, compromising its chondrogenic stability. To address this challenge, we developed a core–shell structured KGN/Gel@Cur/PLCL nanomembrane using coaxial electrospinning technology to enhance the chondrogenic stability of BRC in subcutaneous niche. The shell layer comprises curcumin (Cur), known for its potent immunomodulatory and anti-angiogenic effects, and poly(L-lactide-co-caprolactone) (PLCL). The core layer comprises Kartogenin (KGN), a recognized chondrogenic inducer, and gelatin (Gel). This nanomembrane encapsulated BRCs induced from goat BMSCs in vitro and was subcutaneously implanted into autologous goats. The nanomembrane’s physical barrier and Cur release from the shell layer prevented vascular invasion and inflammatory infiltration. Additionally, KGN release from the core layer maintained the BRC’s chondrogenic phenotype and promoted cartilage maturation. These combined mechanisms significantly inhibited BRC ossification and preserved its chondrogenic stability. chondrogenic phenotype and promoted cartilage maturation. These combined mechanisms significantly inhibited BRC ossification and maintained its chondrogenic stability. Overall, this study highlights the effectiveness of the core–shell structured KGN/Gel@Cur/PLCL nanomembrane in providing sequential immune and vascular isolation, followed with chondrogenic induction, to prevent BRC ossification and preserve the chondrogenic stability of subcutaneously implanted BRC in large animal. This is crucial for the clinical translation of stem cell therapy into subcutaneous cartilage repair.

Suppression of retinal neovascularization by intravitreal injection of cryptotanshinone

Neovascular eye diseases, including proliferative diabetic retinopathy and retinopathy of prematurity, is a major cause of blindness. Laser ablation and intravitreal anti-VEGF injection have shown their limitations in treatment of retinal neovascularization. Identification of a new therapeutic strategies is in urgent need. Our study aims to assess the effects of Cryptotanshinone (CPT), a natural compound derived from Salvia miltiorrhiza Bunge, in retina neovascularization and explore its potential mechanism. Our study demonstrated that CPT did not cause retina tissue toxicity at the tested concentrations. Intravitreal injections of CPT reduced pathological angiogenesis and promoted physical angiogenesis in oxygen-induced retinopathy (OIR) model. CPT improve visual function in OIR mice and reduced cell apoptosis. Moreover, we also revealed that CPT diminishes the expression of inflammatory cytokines in the OIR retina. In vitro, the administration of CPT effectively inhibited endothelial cells proliferation, migration, sprouting, and tube formation induced by the stimulation of human retinal vascular endothelial cells (HRVECs) with VEGF165. Mechanistically, CPT blocking the phosphorylation of VEGFR2 and downstream targeting pathway. After all, the findings demonstrated that CPT exhibits potent anti-angiogenic and anti-inflammatory effects in OIR mice, and it has therapeutic potential for the treatment of neovascular retinal diseases.

Ultrahigh-Efficacy VEGF Neutralization Using Carbonized Nanodonuts: Implications for Intraocular Anti-Angiogenic Therapy.

Ocular angiogenesis, associated with diseases such as retinopathy of prematurity and diabetic retinopathy, is a leading cause of irreversible vision loss. Herein, carbon nanodonuts (CNDs) with a donut-shaped structure are synthesized using sodium alginate (SA) and 1,8-diaminooctane (DAO) through a one-step thermal process. The formation of SA/DAO-CNDs occurs through a crosslinking reaction between SA and DAO, creating amide bonds followed by partial carbonization. In human retinal pigment epithelialcells exposed to H2 O2 or lipopolysaccharide, the SA/DAO-CNDs display a more than fivefold reduction in reactive oxygen species and proinflammatory cytokines, such as IL-6 and IL-1β, when compared to carbonized nanomaterials produced exclusively from SA. Furthermore, the CNDs effectively inhibit vascular endothelial growth factor A-165 (VEGF-A165 )-induced cell migration and tube formation in human umbilical vein endothelial cells due to their strong affinity for VEGF-A165 , with a dissociation constant of 2.2 × 10-14 M, over 1600 times stronger than the commercial drug bevacizumab (Avastin). Trypsin digestion coupled with LC-MS/MS analysis reveals that VEGF-A165 interacts with SA/DAO-CNDs through its heparin-binding domain, leading to activity loss. The SA/DAO-CNDs demonstrate excellent biocompatibility and potent anti-angiogenic effects in chicken embryos and rabbit eyes. These findings suggest that SA/DAO-CNDs hold promise as a therapeutic agent for treating various angiogenesis-related ocular diseases.

Crocetin inhibits choroidal neovascularization in both in vitro and in vivo models

Choroidal neovascularization (CNV) is the primary pathogenic process underlying wet age-related macular degeneration, leading to severe vision loss. Despite current anti-vascular endothelial growth factor (VEGF) therapies, several limitations persist. Crocetin, a major bioactive constituent of saffron, exhibits multiple pharmacological activities, yet its role and mechanism in CNV remain unclear. Here, we investigated the potential effects of crocetin on CNV using in vitro and in vivo models. In human umbilical vein endothelial cells, crocetin demonstrated inhibition of VEGF-induced cell proliferation, migration, and tube formation in vitro, as assessed by CCK-8 and EdU assays, transwell and scratch assays, and tube formation analysis. Additionally, crocetin suppressed choroidal sprouting in ex vivo experiments. In the human retinal pigment epithelium (RPE) cell line ARPE-19, crocetin attenuated cobalt chloride-induced hypoxic cell injury, as evidenced by CCK-8 assay. As evaluated by quantitative PCR and Western blot assay, it also reduced hypoxia-induced expression of VEGF and hypoxia-inducible factor 1α (HIF-1α), while enhancing zonula occludens-1 expression. In a laser-induced CNV mouse model, intravitreal administration of crocetin significantly reduced CNV size and suppressed elevated expressions of VEGF, HIF-1α, TNFα, IL-1β, and IL-6. Moreover, crocetin treatment attenuated the elevation of phospho-S6 in laser-induced CNV and hypoxia-induced RPE cells, suggesting its potential anti-angiogenic effects through antagonizing the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Our findings indicate that crocetin may hold promise as an effective drug for the prevention and treatment of CNV.

A 1, 4-benzoquinone derivative isolated from Ardisia crispa (Thunb.) A. DC. root suppresses angiogenesis via its angiogenic signaling cascades

The root hexane extract of Ardisia crispa (ACRH), which belongs to the Primulaceae family, has been reported to possess anti-inflammatory, chemopreventive, anti-arthritic, and antiangiogenic activities. In this study, we isolated a p-benzoquinone derivative, 2-methoxy-6-undecyl-1,4-benzoquinone (AC2), from ACRH and investigated its potential antiangiogenic activity in human umbilical vein endothelial cells (HUVECs) and zebrafish embryo models. Prior to this study, AC2 was characterized using 1H NMR spectroscopy and MS. AC2 significantly suppressed HUVEC proliferation in a time-independent manner, with an IC50 value of 1.35 ± 0.05, 1.15 ± 0.02, and 1.00 ± 0.01 µg/mL at 24, 48, and 72 h, respectively. AC2 also induced apoptosis in HUVECs and significantly suppressed their migration, invasion, and tube formation in a concentration-dependent manner. Additionally, AC2 significantly attenuated most of the analyzed protein markers, including pro-MMP-2, VEGF-C, VEGF-D, angiopoietin-2, endothelin-1, fibroblast growth factor (FGF)-1, FGF-2, follistatin, heparin-binding epidermal growth factor-like growth factor (HB-EGF), and hepatocyte growth factor (HGF) at all tested concentrations. Furthermore, AC2 significantly inhibited zebrafish embryo intersegmental vessels (ISVs), confirming its antiangiogenic role. In conclusion, AC2 exhibits a potential anti-angiogenic effect by suppressing several proangiogenic and growth factors. Further studies are needed to investigate their effects on other excessive angiogenic diseases.

Molecularly Imprinted Nanomedicine for Anti-angiogenic Cancer Therapy via Blocking Vascular Endothelial Growth Factor Signaling.

The VEGF-VEGFR2 (VEGF = vascular endothelial growth factor) signaling has been a promising target in cancer therapy. However, because conventional anti-angiogenic therapeutics suffer from drawbacks, particularly severe side effects, novel anti-angiogenic strategies are much needed. Herein, we report the rational engineering of VEGF-targeted molecularly imprinted polymer nanoparticles (nanoMIP) for anti-angiogenic cancer therapy. The anti-VEGF nanomedicine was prepared via a state-of-the-art molecular imprinting approach using the N-terminal epitope of VEGF as the template. The nanoMIP could target the two major pro-angiogenic isoforms (VEGF165 and VEGF121) with high affinity and thereby effectively block the VEGF-VEGFR2 signaling, yielding a potent anti-angiogenic effect of "killing two birds with one stone". In vivo experiments demonstrated that the anti-VEGF nanoMIP effectively suppressed tumor growth via anti-angiogenesis in a xenograft model of human colon carcinoma without apparent side effects. Thus, this study not only proposes an unprecedented anti-angiogenic strategy for cancer therapy but also provides a new paradigm for the rational development of MIPs-based "drug-free" nanomedicines.

New indolizidine- and pyrrolidine-type alkaloids with anti-angiogenic activities from Anisodus tanguticus

Eleven alkaloids, including five previously undescribed indolizidine alkaloids (1, 2a, 2b, 3a, and 3b) and four new pyrrolidine alkaloids (5−8), were isolated from the roots of Anisodus tanguticus. Of these, two new pairs of enantiomeric alkaloids (2a/2b and 3a/3b) are the first examples of alkaloids containing both indolizidine and pyrrolidine structural fragments. The one-carbon bridge connections with two pyrrolidine rings (6) or with a pyrrolidine ring and a pyridine ring (8) are the first reported from nature. Extensive spectroscopic techniques were used to elucidate their structures, and NMR and ECD calculations were used to determine the absolute configurations. The viability of human umbilical vein endothelial cells (HUVECs) was inhibited by compounds 2a, 2b, 3a, 4b, and 5, and compound 2b exhibited a potential anti-angiogenic effect by inhibiting the proliferation, migration, and tube formation of HUVECs. A chorioallantoic membrane assay also demonstrated the anti-angiogenic activity of 2b. In addition, compounds 2a, 2b, 3a, and 4b exhibited moderate cytotoxicity against A2780 cells.

Ganetespib (STA-9090) augments sorafenib efficacy via necroptosis induction in hepatocellular carcinoma: Implications from preclinical data for a novel therapeutic approach

Sorafenib, a multikinase inhibitor, is a first-line treatment for advanced hepatocellular carcinoma, but its long-term effectiveness is limited by the emergence of resistance mechanisms. One such mechanism is the reduction of microvessel density and intratumoral hypoxia caused by prolonged sorafenib treatment. Our research has demonstrated that HSP90 plays a critical role in conferring resistance to sorafenib in HepG2 cells under hypoxic conditions and N-Nitrosodiethylamine-exposed mice as well. This occurs through the inhibition of necroptosis on the one hand and the stabilization of HIF-1α on the other hand. To augment the effects of sorafenib, we investigated the use of ganetespib, an HSP90 inhibitor. We found that ganetespib activated necroptosis and destabilized HIF-1α under hypoxia, thus enhancing the effectiveness of sorafenib. Additionally, we discovered that LAMP2 aids in the degradation of MLKL, which is the mediator of necroptosis, through the chaperone-mediated autophagy pathway. Interestingly, we observed a significant negative correlation between LAMP2 and MLKL. These effects resulted in a reduction in the number of surface nodules and liver index, indicating a regression in tumor production rates in mice with HCC. Furthermore, AFP levels decreased. Combining ganetespib with sorafenib showed a synergistic cytotoxic effect and resulted in the accumulation of p62 and inhibition of macroautophagy. These findings suggest that the combined therapy of ganetespib and sorafenib may offer a promising approach for the treatment of hepatocellular carcinoma by activating necroptosis, inhibiting macroautophagy, and exhibiting a potential antiangiogenic effect. Overall, continued research is critical to establish the full therapeutic potential of this combination therapy.

Discovery of novel antibody-drug conjugates bearing tissue protease specific linker with both anti-angiogenic and strong cytotoxic effects

Bevacizumab is an FDA-approved class of monoclonal antibodies used to inhibit angiogenesis and promote normalization of blood vessels. It is usually combined with chemotherapeutic agents to treat a variety of solid tumors. However, the whole-body toxicities and toxicity associated with chemotherapy greatly limit the clinical use of this combination therapy. Antibody-drug conjugates (ADCs) couple monoclonal antibodies to cytotoxic molecules via a linker, utilizing the high specificity of monoclonal antibodies to tumor surface antigens to act as a “biological missile” to deliver chemotherapeutic drugs to the tumor site. Herein, we designed a bevacizumab-based ADC, Bevacizumab Vedotin, conjugating bevacizumab to the microtubulin inhibitor MMAE via a tissue protease-specific linker. Biological studies showed strong stability and good tumor cell targeting of our constructed ADCs; rapid drug release was achieved in the presence of exogenous histone protease B. In addition, Bevacizumab Vedotin exhibited good anti-proliferative, apoptosis-promoting and cell cycle-stalling effects on glioma (U87), hepatocellular carcinoma (HepG2), and breast cancer (MCF-7) cell lines. Further in vitro assays demonstrated the enhanced anti-migration activity against MCF-7, potent anti-angiogenic effects, and blockade of the VEGF/VEGFR pathway of Bevacizumab Vedotin.

Antiangiogenic Activity of Aerva lanata Flowers: In Vitro and In Vivo Evaluation

Background: A well-known traditional herb Aerva lanata is widely used in India for the management of different ailments including urolithiasis. Objective: In the current research, flowers of Aerva lanata were chosen for isolation of active constituents and screened for antiangiogenic and anticancer potentials, as literature supports those flowers have highest quantity of natural constituents when compared with the other parts of the plant. Materials and methods: Hydroalcoholic (80%-water, 20%-alcohol) extract of Aerva Lanata flowers was prepared. Antiangiogenic activity was screened by chick chorioallantoic membrane assay (CAM) (in vivo) and sponge implantation method (SIM) (in vivo). Anti-cancer potency was screened by cell migration (in vitro), tube formation assay (in vitro) and cell proliferation assay (in vitro). Results: The results of test groups were matched up to control group by applying one-way ANOVA, followed by a post hoc and Dunnett’s test. In CAM assay method significant branching points and angiogenic score was obtained at 10-5 M and 10-4 M. Considerable decline was observed in sponge weight, formation of blood vessels and hemoglobin content (Hb)at various concentrations of hydroalcoholic extract of Aerva Lanata flower (HAL) in SIM. The study on human umbilical vein endothelial cells displayed major inhibition of proliferation along with reduction in network length of cord-alike tubes in a dosage-dependent pattern. Conclusions: Aerva lanata has shown potent antiangiogenic and anticancer effect in a dose dependent manner.

Assessing the Antiangiogenic Effects of Chalcones and Their Derivatives

Pathological angiogenesis plays a critical role in tumorigenesis and tumor progression, and anti-angiogenesis therapies have evinced promising antitumor effects in solid tumors. Chalcone skeleton has been regarded as a potential antitumor agent that also targets angiogenesis. In this study, we designed twenty-one non-fluoro-substituted chalcones (13–18, 24–27) and saturated chalcone derivatives (19–23, 28–33) as anti-angiogenic compounds. During the initial stage, these compounds were assessed for their anti-cancer activities against MCF-7 cancer cell lines according to the MTT assay. The compounds revealed satisfactory anti-proliferative capability. An ex vivo fertilized hens’ egg-chorioallantoic membrane (HET-CAM) angiogenic study was conducted for the compounds to gauge their mortality and toxicity, which, in turn, revealed a potent anti-angiogenic effect. Eight compounds (16, 17, 21, 24, 26, 27, 29, and 31) significantly reduced densities of capillaries on CAM, whereas compounds 27 and 29 were the most effective anti-angiogenic agents, when compared with Suramin. Moreover, RT-qPCR analysis demonstrated that the anti-angiogenic activity was associated with the fold changes of VEGFR2. Molecular docking studies were conducted for compounds to investigate their mode of interaction within the binding site of VEGFR-2 kinases. This work provided a basis for further design, structural modification, and development of chalcone derivatives as new anti-angiogenic agents.

Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation.

Isoform-selective histone deacetylase (HDAC) inhibition is promoted as a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC inhibitors. Despite this presumed benefit, considerably more non-selective HDAC inhibitors have undergone clinical trials. In this report, we detail the design and discovery of potent HDAC inhibitors, with 1-benzhydryl piperazine as a surface recognition group, that differ in hydrocarbon linker. In vitro HDAC screening identified two selective HDAC6 inhibitors with nanomolar IC50 values, as well as two non-selective nanomolar HDAC inhibitors. Structure-based molecular modeling was employed to study the influence of linker chemistry of synthesized inhibitors on HDAC6 potency. The breast cancer cell lines (MDA-MB-231 and MCF-7) were used to evaluate compound-mediated in vitro anti-cancer, anti-migratory, and anti-invasive activities. Experiments on the zebrafish MDA-MB-231 xenograft model revealed that a novel non-selective HDAC inhibitor with a seven-carbon-atom linker exhibits potent anti-tumor, anti-metastatic, and anti-angiogenic effects when tested at low micromolar concentrations.

Inhibition of Corneal Neovascularization with the Combination of Aflibercept and Plasmid Pigment Epithelium-Derived Factor-Synthetic Amphiphile INTeraction-18 Vector

Aflibercept, a recent VEGF inhibitor, is a recombinant fusion protein consisting of portions of human VEGF receptors 1 and 2 extracellular domains, fused to the Fc portion of human IgG1 formulated as an iso-osmotic solution for intravitreal administration. In this study, we have estimated that the combination of aflibercept and plasmid pigment epithelium-derived factor-synthetic amphiphile INTeraction-18 (p-PEDF-SAINT-18) has a favorable antiangiogenic effect on corneal neovascularization (NV). Four groups (Group A: 0 μg + 0 μg, B: 0. 1μg + 0.1 μg, C: 1 μg + 1 μg, D: 10 μg + 10 μg) of aflibercept + p-PEDF-SAINT-18 were prepared and implanted into rat subconjunctival substantia propria 1.5 mm from the limbus on the temporal side. The 2 μg of p- bFGF-SAINT-18 were prepared and implanted into the rat corneal stroma 1.5mm from the limbus on the same side. Inhibition of NV was observed and quantified from day 1 to day 90. 18-kDa bFGF and VEGF protein expression was analyzed through biomicroscopic examination, western blot analysis and immunohistochemistry. No inhibition activity for normal limbal vessels was noted. Subconjunctival injection by a combination of aflibercept and p-PEDFSAINT-18 successfully inhibited corneal NV. Successful genes of bFGF and PEDF were expressed through western blot analysis; immunohistochemistry staining showed mild immune response for HLA-DR. We conclude that the combination of aflibercept and p-PEDF-SAINT-18 may have more potent and prolonged antiangiogenic effects, making it possible to reduce the frequency of subconjunctival aflibercept administration, while maintaining relatively high safety and low toxicity.

Characterization of antioxidant, anti-cancer, and immunomodulatory functions of partially purified garlic (Allium sativum L.) lectin

Introduction and Aim: The metabolic and oxidative stress induces highly reactive free radicals that are known to harm normal physiology and play a role in the development of cancer. Elevated levels of these free radicals contribute to excessive neovascularization leading to angiogenesis mediated cancer progression. Targeting these free radicals through dietary source is important strategy in regulation of cancer. Allium sativum L. (AsL) garlic has important multi pharmacological properties. On the other hand, dietary lectins are proven to be the best anti-cancer molecules. The study presents investigation that focus to assess the antioxidant, immunomodulatory and anticancer activities of partially purified garlic lectin (PPAsL). Materials and Methods: Fresh garlic bulbs were processed and evaluated for lectin induced HA activity. Further the garlic lectins (AsL) were partially purified by ammonium sulphate precipitation and dialysis and analyzed through SDS-PAGE. Further lectins were characterized by producing Anti-AsL polyclonal antibodies and purification by affinity chromatography. Pharmacological evaluations of the lectins were assessed through antioxidant, anti-proliferative and antiangiogenic mediated anti-cancer activity. Results: Lectin positive activity was confirmed by HA activity and partial purification lectin identified ?12kDa protein having Glc/Man glycan specificity. The polyclonal antibodies raised against PPAsL, confirmed that it has potent immunogen. Pharmacological evaluation confirmed that PPAsL has potent antioxidant, antiangiogenic and antiproliferative effect both in-vitro and in-vivo. Conclusion: PPAsL is potent antioxidant, anti-proliferative and anti-cancer molecule. The dietary recommendation of the garlic lectin is an important therapeutic strategy against the cancer.

The ability of mucoadhesive gingival patch loaded with EGCG on IL-6 and IL-10 expression in periodontitis.

The mucoadhesive gingival patch is a topical drug delivery process it does not cause any irritation in the mucosa. EGCG (Epigallocatechin-3-gallate) it has potent antioxidant, antiangiogenic and antitumor effects. The present study investigates the ability of mucoadhesive gingival patch loaded with EGCG on periodontitis and its impact on IL-6 and IL-10 expression. Periodontitis model was developed in Wistar rat by induction of Porphyromonas gingivalis. Application of mucoadhesive gingival patch loaded with EGCG (GP-EGCG), mucoadhesive gingival patch loaded with doxycycline (GP-doxy) and blank patch, was done for treated periodontitis 1h each day during 21 days. Indirect immunohistochemical analysis of IL-6 and IL-10 expressions were analyzed in the mandibular preparation of the anterior incisive region of animal. The GP-EGCG treatment for 3 days until 21 days, consistently increased the IL-10 expression in periodontitis (p<0.05). In other hand, GP-EGCG treatment lowered the IL-6 expression after 7, 14 and 21 days (p<0.05). The GP-EGCG is promising for the periodontitis treatment by interfere the IL-6 and IL-10 expression.

A Novel Hypoxia-inducible Factor 1α Inhibitor KC7F2 Attenuates Oxygen-induced Retinal Neovascularization

PurposeKC7F2 is a novel molecule compound that can inhibit the translation of hypoxia-inducible factor 1α (HIF1α). It has been reported to exhibit potential antiangiogenic effect. We hypothesized that KC7F2 could inhibit oxygen-induced retinal neovascularization (RNV). The purpose of this study was to investigate this assumption.MethodsOxygen-induced retinopathy (OIR) models in C57BL/6J mice and Sprague-Dawley rats were used for in vivo study. After intraperitoneal injections of KC7F2, RNV was detected by immunofluorescence and hematoxylin and eosin staining. Retinal inflammation was explored by immunofluorescence. EdU incorporation assay, cell counting kit-8 assay, scratch test, transwell assay, and Matrigel assay were used to evaluate the effect of KC7F2 on the proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVEC) induced by vascular endothelial growth factor (VEGF) in vitro. Protein expression was examined by Western blot.ResultsKC7F2 treatment (10 mg/kg/d) in OIR mice significantly attenuated pathological neovascularization and decreased the number of preretinal neovascular cell nuclei, without changing the avascular area, which showed the same trends in OIR rats. Consistently, after the KC7F2 intervention (10 µM), cell proliferation was inhibited in VEGF-induced HUVEC, which was in agreement with the trend observed in the retinas of OIR mice. Meanwhile, KC7F2 suppressed VEGF-induced HUVEC migration and tube formation, and decreased the density of leukocytes and microglia colocalizing neovascular areas in the retinas. Moreover, the HIF1α–VEGF pathway activated in retinas of OIR mice and hypoxia-induced HUVEC, was suppressed by KC7F2 treatment.ConclusionsThe current study revealed that KC7F2 was able to inhibit RNV effectively via HIF1α–VEGF pathway, suggesting that it might be an effective drug for RNV treatment.

Metformin and retinal diseases in preclinical and clinical studies: Insights and review of literature.

Metformin is one of the most prescribed drugs in the world giving potential health benefits beyond that of type 2 diabetes (T2DM). Emerging evidence suggests that it may have protective effects for retinal/posterior segment diseases including diabetic retinopathy (DR), age-related macular degeneration (AMD), inherited retinal degeneration such as retinitis pigmentosa (RP), primary open angle glaucoma (POAG), retinal vein occlusion (RVO), and uveitis. Metformin exerts potent anti-inflammatory, antiangiogenic, and antioxidative effects on the retina in response to pathologic stressors. In this review, we highlight the broad mechanism of action of metformin through key preclinical studies on animal models and cell lines used to simulate human retinal disease. We then explore the sparse but promising retrospective clinical data on metformin's potential protective role in DR, AMD, POAG, and uveitis. Prospective clinical data is needed to clarify metformin's role in management of posterior segment disorders. However, given metformin's proven broad biochemical effects, favorable safety profile, relatively low cost, and promising data to date, it may represent a new therapeutic preventive and strategy for retinal diseases.

Synthesis, functional proteomics and biological evaluation of new 5-pyrazolyl ureas as potential anti-angiogenic compounds

Based on biological results of previous synthesized pyrazolyl ureas able to interfere with angiogenesis process, we planned and synthesized the new benzyl-urea derivatives 2–4; some of them showed an interesting anti-proliferative profile and particularly 4e potently inhibited HUVEC proliferation. To shed light on the mechanism of action of 4e, its interactome has been deeply inspected to identify the most prominent protein partners, mainly taking into account kinome and phosphatome, through drug affinity responsive target stability experiments, followed by targeted limited proteolysis analysis. From these studies, PP1γ emerged as the most reliable 4e potential target in HUVEC. Molecular docking simulations on PP1γ were carried out to predict 4e binding mode. To assess its potential anti-angiogenic effect, 4e was tested in vitro to verify interference on kinase and phosphate activities. Overall, our results evidenced for 4e an interesting anti-angiogenic action, probably due to its action at intracellular level on PP1γ signalling pathways.