scholarly journals Effects of SGLT2 Inhibition on Diabetic Retinopathy

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Sameer Leley ◽  
Qianyi Luo ◽  
Ashay Bhatwadekar
Keyword(s):  
Diabetic Retinopathy ◽  
Glucose Uptake ◽  
Sglt2 Inhibitor ◽  
In Vitro Models ◽  
Treatment Modalities ◽  
Working Age ◽  
Sglt2 Inhibition ◽  
New Treatment ◽  
Acellular Capillaries

Background and Hypothesis: Diabetic retinopathy (DR), a microvascular complication of diabetes, is the leading cause of blindness in the working-age population, and its prevalence is increasing. New treatment modalities must be developed to slow the progression of DR. SGLT2 inhibition has shown promise in treating other diabetic complications; however, its effect on DR remains unknown, therefore, for this study, we hypothesize that SGLT2 inhibition will reduce the harmful effects of DR. Methods: Diabetic (db/db) mice were fed 10 mg/kg of the SGLT2 inhibitor dapagliflozin in their diet for 6 months, non-diabetic (db/m) mice on a regular diet served as controls. In parallel, human retinal endothelial cells (HREC) were used as in-vitro models and treated with dapagliflozin to assess glucose uptake via a 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2-NBDG) assay. Results: Our studies show that db/db mice with dapagliflozin had significantly fewer acellular capillaries compared to untreated db/db mice. Furthermore, Dapagliflozin treatment at 1 and 10 µM concentrations of dapagliflozin yielded a significant decrease in glucose uptake compared to respective vehicle controls. Conclusion: Our study shows that SGLT2 inhibition has a promise in treating DR by reducing acellular capillaries and retinal glucose transport suggesting the potential of dapagliflozin treatment in DR.

scholarly journals Inhibitory Effects of a Reengineered Anthrax Toxin on Canine Oral Mucosal Melanomas

Toxins ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 157 ◽  
Author(s):  
Adriana Tomoko Nishiya ◽  
Marcia Kazumi Nagamine ◽  
Ivone Izabel Mackowiak da Fonseca ◽  
Andrea Caringi Miraldo ◽  
Nayra Villar Scattone ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Evaluation Criteria ◽  
Anthrax Toxin ◽  
Treatment Modalities ◽  
Inhibitory Effects ◽  
Upa Receptor ◽  
New Treatment ◽  
Oral Malignancy

Canine oral mucosal melanomas (OMM) are the most common oral malignancy in dogs and few treatments are available. Thus, new treatment modalities are needed for this disease. Bacillus anthracis (anthrax) toxin has been reengineered to target tumor cells that express urokinase plasminogen activator (uPA) and metalloproteinases (MMP-2), and has shown antineoplastic effects both, in vitro and in vivo. This study aimed to evaluate the effects of a reengineered anthrax toxin on canine OMM. Five dogs bearing OMM without lung metastasis were included in the clinical study. Tumor tissue was analyzed by immunohistochemistry for expression of uPA, uPA receptor, MMP-2, MT1-MMP and TIMP-2. Animals received either three or six intratumoral injections of the reengineered anthrax toxin prior to surgical tumor excision. OMM samples from the five dogs were positive for all antibodies. After intratumoral treatment, all dogs showed stable disease according to the canine Response Evaluation Criteria in Solid Tumors (cRECIST), and tumors had decreased bleeding. Histopathology has shown necrosis of tumor cells and blood vessel walls after treatment. No significant systemic side effects were noted. In conclusion, the reengineered anthrax toxin exerted inhibitory effects when administered intratumorally, and systemic administration of this toxin is a promising therapy for canine OMM.

scholarly journals Tuning the network charge of biohybrid hydrogel matrices to modulate the release of SDF-1

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Sebastian Kühn ◽  
Joanna Freyse ◽  
Passant Atallah ◽  
Jörg Rademann ◽  
Uwe Freudenberg ◽  
...  
Keyword(s):  
Bone Repair ◽  
Negative Charge ◽  
Polymer Networks ◽  
Signaling Molecules ◽  
Treatment Modalities ◽  
Precise Control ◽  
Integral Density ◽  
New Treatment ◽  
Two Parameters

Abstract The delivery of chemotactic signaling molecules via customized biomaterials can effectively guide the migration of cells to improve the regeneration of damaged or diseased tissues. Here, we present a novel biohybrid hydrogel system containing two different sulfated glycosaminoglycans (sGAG)/sGAG derivatives, namely either a mixture of short heparin polymers (Hep-Mal) or structurally defined nona-sulfated tetrahyaluronans (9s-HA4-SH), to precisely control the release of charged signaling molecules. The polymer networks are described in terms of their negative charge, i.e. the anionic sulfate groups on the saccharides, using two parameters, the integral density of negative charge and the local charge distribution (clustering) within the network. The modulation of both parameters was shown to govern the release characteristics of the chemotactic signaling molecule SDF-1 and allows for seamless transitions between burst and sustained release conditions as well as the precise control over the total amount of delivered protein. The obtained hydrogels with well-adjusted release profiles effectively promote MSC migration in vitro and emerge as promising candidates for new treatment modalities in the context of bone repair and wound healing.

scholarly journals Stem Cells and Gene Therapy in Progressive Hearing Loss: the State of the Art

2021 ◽  
Author(s):  
Aida Nourbakhsh ◽  
Brett M. Colbert ◽  
Eric Nisenbaum ◽  
Aziz El-Amraoui ◽  
Derek M. Dykxhoorn ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gene Therapy ◽  
Hearing Loss ◽  
Treatment Modalities ◽  
Versus Gene ◽  
Vitro Model ◽  
New Treatment ◽  
Induced Pluripotent ◽  
Therapy Strategies

AbstractProgressive non-syndromic sensorineural hearing loss (PNSHL) is the most common cause of sensory impairment, affecting more than a third of individuals over the age of 65. PNSHL includes noise-induced hearing loss (NIHL) and inherited forms of deafness, among which is delayed-onset autosomal dominant hearing loss (AD PNSHL). PNSHL is a prime candidate for genetic therapies due to the fact that PNSHL has been studied extensively, and there is a potentially wide window between identification of the disorder and the onset of hearing loss. Several gene therapy strategies exist that show potential for targeting PNSHL, including viral and non-viral approaches, and gene editing versus gene-modulating approaches. To fully explore the potential of these therapy strategies, a faithful in vitro model of the human inner ear is needed. Such models may come from induced pluripotent stem cells (iPSCs). The development of new treatment modalities by combining iPSC modeling with novel and innovative gene therapy approaches will pave the way for future applications leading to improved quality of life for many affected individuals and their families.

scholarly journals Advanced Spheroid, Tumouroid and 3D Bioprinted In-Vitro Models of Adult and Paediatric Glioblastoma

2021 ◽  
Vol 22 (6) ◽  
pp. 2962
Author(s):  
Louise Orcheston-Findlay ◽  
Samuel Bax ◽  
Robert Utama ◽  
Martin Engel ◽  
Dinisha Govender ◽  
...  
Keyword(s):  
Life Expectancy ◽  
High Throughput Screening ◽  
High Grade Glioma ◽  
Tumour Microenvironment ◽  
In Vitro Models ◽  
Treatment Modalities ◽  
High Grade ◽  
Future Improvement ◽  
Complex Models

The life expectancy of patients with high-grade glioma (HGG) has not improved in decades. One of the crucial tools to enable future improvement is advanced models that faithfully recapitulate the tumour microenvironment; they can be used for high-throughput screening that in future may enable accurate personalised drug screens. Currently, advanced models are crucial for identifying and understanding potential new targets, assessing new chemotherapeutic compounds or other treatment modalities. Recently, various methodologies have come into use that have allowed the validation of complex models—namely, spheroids, tumouroids, hydrogel-embedded cultures (matrix-supported) and advanced bioengineered cultures assembled with bioprinting and microfluidics. This review is designed to present the state of advanced models of HGG, whilst focusing as much as is possible on the paediatric form of the disease. The reality remains, however, that paediatric HGG (pHGG) models are years behind those of adult HGG. Our goal is to bring this to light in the hope that pGBM models can be improved upon.

The effect of acute dual SGLT1/SGLT2 inhibition on incretin release and glucose metabolism after gastric bypass surgery

2020 ◽  
Vol 318 (6) ◽  
pp. E956-E964
Author(s):  
Christoffer Martinussen ◽  
Simon Veedfald ◽  
Carsten Dirksen ◽  
Kirstine N. Bojsen-Møller ◽  
Maria S. Svane ◽  
...  
Keyword(s):  
Gastric Bypass ◽  
Glucose Metabolism ◽  
Hormone Secretion ◽  
Sglt2 Inhibitor ◽  
Area Under The Curve ◽  
Glucose Absorption ◽  
Oral Glucose ◽  
Glucose Ingestion ◽  
Sglt2 Inhibition

Enhanced meal-related enteroendocrine secretion, particularly of glucagon-like peptide-1 (GLP-1), contributes to weight-loss and improved glycemia after Roux-en-Y gastric bypass (RYGB). Dietary glucose drives GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretion postoperatively. Understanding how glucose triggers incretin secretion following RYGB could lead to new treatments of diabetes and obesity. In vitro, incretin release depends on glucose absorption via sodium-glucose cotransporter 1 (SGLT1). We investigated the importance of SGLT1/SGLT2 for enteropancreatic hormone concentrations and glucose metabolism after RYGB in a randomized, controlled, crossover study. Ten RYGB-operated patients ingested 50 g of oral glucose with and without acute pretreatment with 600 mg of the SGLT1/SGLT2-inhibitor canagliflozin. Paracetamol and 3- O-methyl-d-glucopyranose (3-OMG) were added to the glucose drink to evaluate rates of intestinal entry and absorption of glucose, respectively. Blood samples were collected for 4 h. The primary outcome was 4-h plasma GLP-1 (incremental area-under the curve, iAUC). Secondary outcomes included glucose, GIP, insulin, and glucagon. Canagliflozin delayed glucose absorption (time-to-peak 3-OMG: 50 vs. 132 min, P < 0.01) but did not reduce iAUC GLP-1 (6,067 vs. 7,273·min·pmol−1·L−1, P = 0.23), although peak GLP-1 concentrations were lowered (−28%, P = 0.03). Canagliflozin reduced GIP (iAUC −28%, P = 0.01; peak concentrations −57%, P < 0.01), insulin, and glucose excursions, whereas plasma glucagon (AUC 3,216 vs. 4,160 min·pmol·L−1, P = 0.02) and amino acids were increased. In conclusion, acute SGLT1/SGLT2-inhibition during glucose ingestion did not reduce 4-h plasma GLP-1 responses in RYGB-patients but attenuated the early rise in GLP-1, GIP, and insulin, whereas late glucagon concentrations were increased. The results suggest that SGLT1-mediated glucose absorption contributes to incretin hormone secretion after RYGB.

Tenilsetam prevents early diabetic retinopathy without correcting pericyte loss

2006 ◽  
Vol 95 (04) ◽  
pp. 689-695 ◽  
Author(s):  
Jennifer Hoffmann ◽  
Alex Alt ◽  
Jihong Lin ◽  
Günther Lochnit ◽  
Uwe Schubert ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Diabetic Retinopathy ◽  
Endothelial Cell ◽  
Vegf Expression ◽  
Endothelial Proliferation ◽  
High Doses ◽  
Acellular Capillaries ◽  
Pericyte Loss ◽  
The Impact

SummaryHyperglycemia-induced mitochondrial overproduction of reactive oxygen species leads to the activation of different biochemical pathways involved in endothelial damage of the diabetic retina. Tenilsetam [(±)-3-(2-thienyl)-2-piperazinone] is a dicarbonyl scavenger in the millimolar range anda transition metal ion chelator in the micromolar range. We tested its effect on experimental diabetic retinopathy, and on endothelial cell characteristics in vitro. Streptozotocin diabetic male Wistar rats (60 mg/ kg BW) received 50 mg/kg BW tenilsetam (D-T) for 36 weeks, or no treatment (D).The impact of tenilsetam (0–30 mM) on endothelial proliferation, apoptosis, sprouting, cytokine-induced leucocyte-endothelial interaction, and VEGF expression was tested in vitro.Tenilsetam did not affect glycemic control or body weight in diabetic animals. The 3.7 fold increase in acellular capillaries in diabetic rats [p<0.001 vs. non-diabetic controls (N)] was reduced by 70% (p<0.001) through treatment, but pericyte loss (D vs. N –33%; p<0.001) remained unaffected. In vitro, tenilsetam inhibited endothelial proliferation at lower doses, while inducing apoptosis at high doses. Leucocyte adhesion was only inhibited at high doses. Sprouting angiogenesis of bovine retinal endothelial cells was promoted at lower doses (≤ 10 mM). At micromolar concentrations, endothelial VEGF expression was upregulated by 100%. Long-term treatment with the AGEinhibitor and iron-chelating compound tenilsetam inhibits the formation of acellular capillaries without correcting pericyte loss. The compound has dose-dependent effects on endothelial cell function. These data suggest that, independent of known properties, tenilsetam shows important rescue functions on endothelial cells which could be useful for the treatment of early diabetic retinopathy.

scholarly journals Stem Cell Treatment and Gene Therapy in Diabetic Retinopathy

2018 ◽  
pp. 189-193
Keyword(s):  
Diabetic Retinopathy ◽  
Stem Cell ◽  
Single Gene ◽  
Gene Mutations ◽  
Limiting Factors ◽  
Treatment Modalities ◽  
Severe Visual Loss ◽  
Gene Treatment ◽  
New Treatment ◽  
Stem Cell Treatment

New treatment modalities have been under investigation in patients with diabetic retinopathy whose severe visual loss cannot be prevented despite the strict metabolic control and all treatment modalities currently used. It is shown that stem cell applications can be able to prevent the retinopathy progression in studies on diabetic models of experimental animals. However, there is no clinical study on this regard in the literature up to date. Gene treatment studies have mostly focused on ocular pathologies that result in single-gene mutations. The main limiting factors for these studies are that, diabetic retinopathy is polygenic and relatively heterogeneous. and has complex pathogenesis, and lasts for many years.

scholarly journals Repositioning therapy for thyroid cancer: new insights on established medications

2014 ◽  
Vol 21 (3) ◽  
pp. R183-R194 ◽  
Author(s):  
Yevgeniya Kushchayeva ◽  
Kirk Jensen ◽  
Kenneth D Burman ◽  
Vasyl Vasko
Keyword(s):  
Thyroid Cancer ◽  
Treatment Modalities ◽  
Multiple Cancer ◽  
Sexually Transmitted ◽  
Individualized Approach ◽  
Cancer Types ◽  
New Treatment ◽  
Derivatives Of

Repositioning of established non-cancer pharmacotherapeutic agents with well-known activity and side-effect profiles is a promising avenue for the development of new treatment modalities for multiple cancer types. We have analyzed some of the medications with mechanism of action that may have relevance to thyroid cancer (TC). Experimentalin vitroandin vivoevidences, as well as results of clinical studies, have indicated that molecular targets for medications currently available for the treatment of mood disorders, sexually transmitted diseases, metabolic disorders, and diabetes may be active and relevant in TC. For instance, the derivatives of cannabis and an anti-diabetic agent, metformin, both are able to inhibit ERK, which is commonly activated in TC cells. We present here several examples of well-known medications that have the potential to become new therapeutics for patients with TC. Repositioning of established medications for the treatment of TC could broaden the scope of current therapeutic strategies. These diverse treatment choices could allow physicians to provide an individualized approach to optimize treatment for patients with TC.

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