Neovascular age-related macular degeneration (nvAMD) is the leading cause of severe vision loss in the elderly in the developed world. While the introduction of therapies targeting vascular endothelial growth factor (VEGF) has provided the first opportunity to significantly improve vision in patients with nvAMD, many patients respond inadequately to current anti-VEGF therapies. It was recently demonstrated that expression of a second angiogenic mediator, angiopoietin-like 4 (ANGPTL4), synergizes with VEGF to promote choroidal neovascularization (CNV) in mice and correlates with reduced response to anti-VEGF therapy in patients with nvAMD. Here, we report that expression of ANGPTL4 in patients with nvAMD increases following treatment with anti-VEGF therapy and that this increase is dependent on accumulation of hypoxia-inducible factor (HIF)-1α in response to inhibition of VEGF/KDR signaling in the retinal pigment epithelium (RPE). We therefore explored HIF-1 inhibition with 32-134D, a recently developed pharmacologic HIF-inhibitor, for the treatment of nvAMD. 32-134D prevented the expression of both VEGF and ANGPTL4 and was at least as effective as aflibercept in treating CNV in mice. Moreover, by preventing the increase in HIF-1α accumulation in the RPE in response to anti-VEGF therapy, combining 32-134D with aflibercept was more effective than either drug alone for the treatment of CNV. Collectively, these results help explain why many patients with nvAMD respond inadequately to anti-VEGF therapy and suggest that the HIF inhibitor 32-134D will be an effective drug—alone or in combination with current anti-VEGF therapies—for the treatment of patients with this blinding disease.

The blood-retinal barrier (BRB) serves as a physiological boundary regulating the passage of nutrients, waste, ions, proteins, and water to and from the retina. In patients with diabetic retinopathy, breakdown of the inner BRB (iBRB) results in damage to the neurovascular unit and is a principal cause of vision loss in the diabetic population. Here, we demonstrate that hypoglycemia, a common consequence of tight glycemic control and high glycemic variability, results in accumulation of the transcription factors hypoxia-inducible factor-1α (HIF-1α) and HIF-2α and the expression of dozens of HIF-dependent vasoactive mediators in the mouse retina. In diabetic mice, this modest increase in HIF-dependent hyperpermeability factors was sufficient to promote vesicular transcytosis, breakdown of the iBRB, and retinal vascular permeability. Genetic inhibition of either HIF-1α or HIF-2α resulted in an incomplete inhibition of the broad increase in HIF-regulated vasoactive gene expression in response to hypoglycemia. We therefore evaluated a pharmacologic dual HIF-1 and HIF-2 inhibitor, 32-134D, as a therapeutic approach to prevent hypoglycemia-induced HIF-dependent vasoactive gene expression. 32-134D effectively inhibited HIF-1α accumulation and HIF-regulated gene expression in human retinal tissue. In diabetic mice, intravitreal administration of 32-134D prevented the increase in expression of HIF-regulated vasoactive genes after transient episodes of hypoglycemia, blocking both breakdown of the iBRB and the promotion of retinal vascular hyperpermeability. Collectively, these observations help explain why patients with diabetes initiating tight glycemic control have worsening of their diabetic retinopathy and provide the foundation for clinical studies assessing HIF inhibition with 32-134D for its prevention.

Angiogenesis, neovascularization, and vascular remodeling are highly dynamic processes, where endothelial cell–cell adhesion within the vessel wall controls a range of physiological processes, such as growth, integrity, and barrier function. The cadherin–catenin adhesion complex is a key contributor to inner blood–retinal barrier (iBRB) integrity and dynamic cell movements. However, the pre-eminent role of cadherins and their associated catenins in iBRB structure and function is not fully understood. Using a murine model of oxygen-induced retinopathy (OIR) and human retinal microvascular endothelial cells (HRMVECs), we try to understand the significance of IL-33 on retinal endothelial barrier disruption, leading to abnormal angiogenesis and enhanced vascular permeability. Using electric cell-substrate impedance sensing (ECIS) analysis and FITC-dextran permeability assay, we observed that IL-33 at a 20 ng/mL concentration induced endothelial-barrier disruption in HRMVECs. The adherens junction (AJs) proteins play a prominent role in the selective diffusion of molecules from the blood to the retina and in maintaining retinal homeostasis. Therefore, we looked for the involvement of adherens junction proteins in IL-33-mediated endothelial dysfunction. We observed that IL-33 induces α-catenin phosphorylation at serine/threonine (Ser/Thr) residues in HRMVECs. Furthermore, mass-spectroscopy (MS) analysis revealed that IL-33 induces the phosphorylation of α-catenin at Thr⁶⁵⁴ residue in HRMVECs. We also observed that PKCμ/PRKD1-p38 MAPK signaling regulates IL-33-induced α-catenin phosphorylation and retinal endothelial cell-barrier integrity. Our OIR studies revealed that genetic deletion of IL-33 resulted in reduced vascular leakage in the hypoxic retina. We also observed that the genetic deletion of IL-33 reduced OIR-induced PKCμ/PRKD1-p38 MAPK-α-catenin signaling in the hypoxic retina. Therefore, we conclude that IL-33-induced PKCμ/PRKD1-p38 MAPK-α-catenin signaling plays a significant role in endothelial permeability and iBRB integrity.

Drug chemoresistance remains a major reason of treatment failure in cancer patients. In head and neck squamous cell carcinoma (HNSCC), the seventh most common cancer worldwide, cisplatin chemotherapy remains the gold standard for advanced tumors but often faces loss of responsiveness and the drawback of relapse. We previously showed that the metabolic and angiogenic factor angiopoietin-like 4 (ANGPTL4) is a molecular biomarker of oral dysplasia and HNSCC. We also found that through interaction with Neuropilin 1 (NRP1), ANGPTL4 activates proliferative and migratory pathways that contribute to HNSCC development. Using HNSCC xenografts, patient tumor-derived organoids, tumor spheroids, and HNSCC cell lines, CAL27, HN13, and HN4, here we provide evidence of the role of ANGPTL4 in the development of platinum-based chemoresistance in HNSCC through the promotion of DNA damage response (DDR) and homologous recombination (HR). ANGPTL4 enhanced these mechanisms by promoting phosphorylation of RAD51 recombinase in Tyr ^315/54 through an NRP1/ABL1-dependent mechanism. Pharmacologic inhibition of NRP1 or ABL1 reversed ANGPTL4-mediated DDR and HR, and increased HNSCC cell death in combination with cisplatin, in vitro and in vivo. Our results reveal a role for ANGPTL4 in RAD51-dependent DNA repair and suggest that ANGPTL4/NRP1/ABL1/RAD51 may serve as an alternative therapeutic target for HNSCC.

Background and purpose - Parkinson’s disease with cardinal feature of bradykinesia is a movement disorder. The effect of cueing in disorders like parkinsons patients ,stroke, spinal cord injury for improving motor skills and gait and lower limb functions have long been investigated by the Researchers, but there are dearth of studies evaluating the effect of cueing on fine motor skills in patients with parkinson’s disease. Hence this study tries to investigate the effect of auditory cueing on fine motor skills in Parkinson’s disease. Methodology - 25 diagnosed Parkinson’s patients having primary level of education, with mean age 72±5 yrs in Hoehn and Yahr stages 1 to 3 of disease and MMSE score above 24 were included in the study. Two groups were formed; one group performing activities with auditory cueing and other group performing activities without auditory cueing. Scores were calculated using Jebsen Taylor Hand Function Test. Results - Mean values of pre and post intervention timings on Jebsen Taylor Hand Function Test were calculated. Group with auditory cueing showed improvement in total sores of subtests of Jebsen Taylor Hand Function Test with mean and standard deviation (58.51±2.69) seconds in dominant hand and (54.59±2.43) seconds in non-dominant hand, whereas, Group without auditory cueing showed improvement in total sores of subtests of Jebsen Taylor Hand Function Test with mean and standard deviation of (13.39±2.07) seconds in dominant hand and (13.52±1.96) seconds in non-dominant hand. Conclusion- Auditory cueing is proved to be an effective method in improving fine motor skills in patients with Parkinsons disease.