scholarly journals Silencing of miR-20b-5p Exerts Inhibitory Effect on Diabetic Retinopathy via Inactivation of THBS1 Gene Induced VEGF/Akt/PI3K Pathway

2021 ◽  
Vol Volume 14 ◽  
pp. 1183-1193
Author(s):  
YanBo Ma ◽  
ChunYing Dong ◽  
XiHui Chen ◽  
RuiXi Zhu ◽  
Jie Wang
Keyword(s):  
Diabetic Retinopathy ◽  
Inhibitory Effect ◽  
Pi3k Pathway

Dantrolene Potentiates the Antineoplastic Effect of Sorafenib in Hepatocellular Carcinoma via Targeting Ca+2/PI3K Signaling Pathway

2021 ◽  
Vol 14 ◽  
Author(s):  
Sherin Zakaria ◽  
Abeer Ansary ◽  
Nabil M. Abdel-Hamid ◽  
Mamdouh M. ElShishtawy
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cyclin D1 ◽  
Antineoplastic Agent ◽  
Inhibitory Effect ◽  
Pi3k Pathway ◽  
Ki 67 ◽  
Antineoplastic Effect ◽  
Pi3k Signaling Pathway ◽  
Proliferation And Metastasis

Background: Hepatocellular carcinoma (HCC) is the 6th prevalent cancer and the 4th leading cause of cancer related deaths all over the world. A major challenge for sorafenib, the standard chemotherapeutic agent in HCC treatment, is the chemo-resistance. Objective: This study was conducted to evaluate the role of dantrolene as a possible antineoplastic agent in HCC, and in chemo-sensitization of sorafenib via targeting Ca+2/PI3K pathway. Methods: HCC was induced in rats using a single dose of diethyl nitrosamine (DENA) (200 mg/kg, ip), followed by phenobarbital sodium (0.05%) in drinking water for 18 weeks. At the end of 18th week, rats were allocated into 4 groups (10 rats/each), one group was left without treatment (DENA group) and the other three groups were treated with either sorafenib, dantrolene, or their combination for further 4 weeks. One day after last injection, serum and liver tissues were collected. Liver tissue p53, VEGF, MMP-9, Cyclin D1, PI3K, and, serum AFP were assessed using immunoassay. Hepatic and serum Ca+2 were also computed. Furthermore, Ki67 was assessed immunohistochemically. Results: Dantrolene exhibited synergistic effect when used in combination with sorafenib compared to either drug alone (p <0.05) through decreasing p53, VEGF, MMP-9, Cyclin D1, and Ki-67. In addition, dantrolene was evidenced to have an inhibitory effect on Ca+2/PI3K pathway that mediates its antineoplastic action when used alone or in combination with sorafenib. Conclusion: Dantrolene exerted antineoplastic effect as well as augmented sorafenib antineoplastic activity via intervention of Ca+2/PI3K pathway, manifested by ameliorating angiogenesis, apoptosis, proliferation and metastasis.

scholarly journals Evogliptin, a dipeptidyl peptidase-4 inhibitor, attenuates pathological retinal angiogenesis by suppressing vascular endothelial growth factor-induced Arf6 activation

2020 ◽  
Vol 52 (10) ◽  
pp. 1744-1753
Author(s):  
Songyi Seo ◽  
Mi-Kyung Kim ◽  
Ryul-I Kim ◽  
Yeongju Yeo ◽  
Koung Li Kim ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Diabetic Retinopathy ◽  
Growth Factor ◽  
Dipeptidyl Peptidase ◽  
Inhibitory Effect ◽  
Retinal Neovascularization ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Dipeptidyl Peptidase 4 ◽  
Endothelial Growth Factor

Abstract Dipeptidyl peptidase-4 (DPP-4) inhibitors are used for the treatment of type 2 diabetes mellitus (DM). Recent studies have shown that beyond their effect in lowing glucose, DPP-4 inhibitors mitigate DM-related microvascular complications, such as diabetic retinopathy. However, the mechanism by which pathological retinal neovascularization, a major clinical manifestation of diabetic retinopathy, is inhibited is unclear. This study sought to examine the effects of evogliptin, a potent DPP-4 inhibitor, on pathological retinal neovascularization in mice and elucidate the mechanism by which evogliptin inhibits angiogenesis mediated by vascular endothelial growth factor (VEGF), a key factor in the vascular pathogenesis of proliferative diabetic retinopathy (PDR). In a murine model of PDR, an intravitreal injection of evogliptin significantly suppressed aberrant retinal neovascularization. In human endothelial cells, evogliptin reduced VEGF-induced angiogenesis. Western blot analysis showed that evogliptin inhibited the phosphorylation of signaling molecules associated with VEGF-induced cell adhesion and migration. Moreover, evogliptin substantially inhibited the VEGF-induced activation of adenosine 5′-diphosphate ribosylation factor 6 (Arf6), a small guanosine 5′-triphosphatase (GTPase) that regulates VEGF receptor 2 signal transduction. Direct activation of Arf6 using a chemical inhibitor of Arf-directed GTPase-activating protein completely abrogated the inhibitory effect of evogliptin on VEGF-induced activation of the angiogenic signaling pathway, which suggests that evogliptin suppresses VEGF-induced angiogenesis by blocking Arf6 activation. Our results provide insights into the molecular mechanism of the direct inhibitory effect of the DPP-4 inhibitor evogliptin on pathological retinal neovascularization. In addition to its glucose-lowering effect, the antiangiogenic effect of evogliptin could also render it beneficial for individuals with PDR.

scholarly journals Aldose Reductase Inhibitiory Effect of Gymnemic Acid, Trigonelline and Ferulic Acid- An In Silico Approach

2017 ◽  
Vol 9 (1) ◽  
Author(s):  
Roshana Devi Vellai ◽  
Subramanian Sorimuthu Pillai
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Retinopathy ◽  
Ferulic Acid ◽  
Aldose Reductase ◽  
In Silico ◽  
Inhibitory Effect ◽  
Computational Method ◽  
Gymnemic Acid ◽  
Chronic Hyperglycemia

Diabetic retinopathy (DR) is one of the earliest complications of chronic hyperglycemia and is a major cause of vision loss. Nearly all patients with type 1 diabetes mellitus and more than 60 % with chronic type 2 diabetes develop some degree of retinopathy after 10 years. Aldose reductase, the first enzyme in polyol pathway chiefly contributes to the development of diabetic retinopathy and other secondary complications. None of the currently available drugs used to inhibit the activity of aldose reductase is found to be ideal due to their adverse effects. Hence, the screening and identification of more effective and safer aldose reductase inhibitors from natural products have been critical requirement in the management and treatment of T2DM. Recently, we have reported the antidiabetic properties of phytochemicals such as Gymnemic acid, Trigonelline and Ferulic acid in high fat diet fed- low dose STZ induced experimental type 2 diabetes in rats. In the present study, the structure based computational method was employed to identify the in silico inhibitory effect of the above phytoingredients on aldose reductase activity. Auto Dock 4.2 is used to study the molecular interactions between the ligands and the receptor. The data obtained evidenced that the docking efficacy of the antidiabetic ligands which are comparable with fidarestat, the standard used in the present study. Thus, the antidiabetic properties of the above lead molecules may attribute to its aldose reductase inhibitory effect.

Inhibitory Potential of Dietary Nutraceuticals on Cellular PI3K/Akt Signaling: Implications in Cancer Prevention and Therapy

2021 ◽  
Vol 21 ◽  
Author(s):  
Arunaksharan Narayanankutty
Keyword(s):  
Natural Products ◽  
Cancer Prevention ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Dietary Intervention ◽  
Phosphatidyl Inositol ◽  
Cancer Chemoprevention ◽  
Inhibitory Effect ◽  
Pi3k Pathway ◽  
Mtor Pathway

Background: : The phosphatidyl inositol-3 kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) signaling have been associated with many cellular physiological events such as proliferation, maturation, survival, and metabolism. Besides their roles in normal cells, the pathway is often upregulated in various cancers. Due to their prominent roles in the cancer progression events, it is now being considered a target for cancer therapy and cancer chemoprevention. Objectives: : The present review provides a concise outline of the role of the PI3K/Akt/mTOR pathway in carcinogenesis and progression events, including metastasis, drug resistance, and stemness. Further, emphasis is given to the PI3K/Akt/mTOR pathway inhibitory potentials of various food-derived bioactive components in cancer prevention. Methods: : Data on the PI3K/Akt/mTOR inhibiting natural products and their bioactive compounds have been obtained from PubMed/Medline, Scopus, Eurekaselect, etc. Findings from the above citation databases from 2000-2021 are included in the manuscript. Results:: Numerous compounds from plants have been isolated and identified as anticancer agents; among these, a predominant class is nutraceuticals. The PI3K pathway is the principal target of these natural products, and many of these drug candidates are under various stages of drug development. These compounds have shown a significant inhibitory effect on the kinase activities of PI3K and Akt, resulting in the abrogation of cancer initiation and progression events. In addition, these compounds have been shown to reverse the resistance to chemotherapeutic drugs and reduce the population of cancer stem cells. Conclusion: : The nutraceuticals are promising candidates as anticancer agents by blocking PI3K signaling cascades. As the PI3K is a central pathway to various receptor signaling, the dietary intervention may prove highly effective.

scholarly journals miR-125a-5p attenuates macrophage-mediated vascular dysfunction by targeting Ninjurin1

2022 ◽  
Author(s):  
Su Jung Hwang ◽  
Bum Ju Ahn ◽  
Min-Wook Shin ◽  
Ye-Seul Song ◽  
Youngbin Choi ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Inflammatory Diseases ◽  
Vascular Dysfunction ◽  
Expression Patterns ◽  
Cell Formation ◽  
Inhibitory Effect ◽  
Vascular Network ◽  
Inflammatory Factors ◽  
Vascular Integrity

AbstractNinjurin1 (Ninj1), an adhesion molecule, regulates macrophage function in hyaloid regression, multiple sclerosis, and atherosclerosis. However, its biological relevance and the mechanism underlying its function in vascular network integrity have not been studied. In this study, we investigated the role of Ninj1 in physiological (postnatal vessel formation) and pathological (endotoxin-mediated inflammation and diabetes) conditions and developed a strategy to regulate Ninj1 using specific micro (mi)RNAs under pathological conditions. Ninj1-deficient mice exhibited decreased hyaloid regression, tip cell formation, retinal vascularized area, recruitment of macrophages, and endothelial apoptosis during postnatal development, resulting in delayed formation of the vascular network. Five putative miRNAs targeting Ninj1 were selected using the miRanda algorithm and comparison of expression patterns. Among them, miR-125a-5p showed a profound inhibitory effect on Ninj1 expression, and miR-125a-5p mimic suppressed the cell-to-cell and cell-to-matrix adhesion of macrophages and expression of pro-inflammatory factors mediated by Ninj1. Furthermore, miR-125a-5p mimic inhibited the recruitment of macrophages into inflamed retinas in endotoxin-induced inflammation and streptozotocin-induced diabetes in vivo. In particular, miR-125a-5p mimic significantly attenuated vascular leakage in diabetic retinopathy. Taken together, these findings suggest that Ninj1 plays a pivotal role in macrophage-mediated vascular integrity and that miR-125a-5p acts as a novel regulator of Ninj1 in the management of inflammatory diseases and diabetic retinopathy.

Aflibercept for the Treatment of Diabetic Retinopathy and Diabetic Macular Edema

2018 ◽  
pp. 147-154
Keyword(s):  
Diabetic Retinopathy ◽  
Growth Factor ◽  
Macular Edema ◽  
Diabetic Macular Edema ◽  
Vision Loss ◽  
Developed Countries ◽  
Inhibitory Effect ◽  
Duration Of Action ◽  
Anti Vegf ◽  
Working Age

Diabetic macular edema (DME) is a common complication of diabetic retinopathy (DR) and is a leading cause of vision loss in developed countries during the working age. Understanding the role of vascular endothelial growth factor (VEGF) in the pathogenesis of DME has emphasized the importance of using anti-VEGF agents in treatment. Anti-VEGF drugs such as pegaptanib, ranibizumab, bevacizumab, and aflibercept have been studied in the treatment of DME. Aflibercept is a recombinant fusion protein with an inhibitory effect on VEGF-A, VEGF-B, placental growth factor (PIGF) 1 and 2. It is believed that this agent has a longer duration of action than other anti-VEGF molecules due to its high-affinity binding to the VEGF molecule. This review summarizes the pharmacological properties of aflibercept in terms of clinical efficacy, use, and tolerability in the treatment of DME.

scholarly journals Potential Therapeutic Roles for Inhibition of the PI3K/Akt/mTOR Pathway in the Pathophysiology of Diabetic Retinopathy

2011 ◽  
Vol 2011 ◽  
pp. 1-19 ◽  
Author(s):  
Jorge L. Jacot ◽  
David Sherris
Keyword(s):  
Diabetic Retinopathy ◽  
Mtor Inhibitors ◽  
Inhibitory Effect ◽  
Mtor Pathway ◽  
Blood Retinal Barrier ◽  
Pathological Angiogenesis ◽  
Dosing Frequency ◽  
Favorable Safety ◽  
Chronic Drug Administration ◽  
Chronic Use

Novel therapeutics such as inhibitors of PI3K/Akt/mTOR pathway presents a unique opportunity for the management of diabetic retinopathy (DR). Second generation mTOR inhibitors have the prospect to be efficacious in managing various stages of disease progression in DR. During early stages, the mTOR inhibitors suppress HIF-1α, VEGF, leakage, and breakdown of the blood-retinal barrier. These mTOR inhibitors impart a pronounced inhibitory effect on inflammation, an early component with diverse ramifications influencing the progression of DR. These inhibitors suppress IKK and NF-κB along with downstream inflammatory cytokines, chemokines, and adhesion molecules. In proliferative DR, mTOR inhibitors suppress several growth factors that play pivotal roles in the induction of pathological angiogenesis. Lead mTOR inhibitors in clinical trials for ocular indications present an attractive treatment option for chronic use in DR with favorable safety profile and sustained ocular pharmacokinetics following single dose. Thereby, reducing dosing frequency and risk associated with chronic drug administration.

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