Sorbinil, an Aldose Reductase Inhibitor, in Fighting Against Diabetic Complications

2019 ◽  
Vol 15 (1) ◽  
pp. 3-7 ◽  
Author(s):  
Qi Huang ◽  
Qiong Liu ◽  
Dongsheng Ouyang
Keyword(s):  
Aldose Reductase ◽  
Diabetic Complications ◽  
Polyol Pathway ◽  
Review Article ◽  
Global Public Health ◽  
Model Studies ◽  
Human Use ◽  
Pathway Inhibition

Background: Aldose reductase (AR) is involved in the pathogenesis of diabetes, which is one of the major threats to global public health. Objective: In this review article, we have discussed the role of sorbinil, an AR inhibitor (ARI), in preventing diabetic complications. Results: AR contributes in diabetes by generating excess intracellular superoxide and other mediators of oxidative stress through polyol pathway. Inhibition of AR activity thus might be a potential approach for the management of diabetic complications. Experimental evidences indicated that sorbinil can decrease AR activity and inhibit polyol pathway. Both in vitro and animal model studies reported the efficacy of sorbinil in controlling the progression of diabetes. Moreover, Sorbinil has been found to be comparatively safer than other ARIs for human use. But, it is still in earlyphase testing for the treatment of diabetic complications clinically. Conclusion: Sorbinil is an effective ARI, which could play therapeutic role in treating diabetes and diabetic complications. However, advanced clinical trials are required for sorbinil so that it could be applied with the lowest efficacious dose in humans.

scholarly journals Curcumin Analogues with Aldose Reductase Inhibitory Activity: Synthesis, Biological Evaluation, and Molecular Docking

Processes ◽  
2019 ◽  
Vol 7 (7) ◽  
pp. 417 ◽  
Author(s):  
Dasharath Kondhare ◽  
Sushma Deshmukh ◽  
Harshad Lade
Keyword(s):  
Molecular Docking ◽  
Aldose Reductase ◽  
Diabetic Complications ◽  
Curcuma Longa ◽  
Polyol Pathway ◽  
Biological Evaluation ◽  
Curcumin Analogues ◽  
Ic50 Values ◽  
Rate Limiting

Curcumin, a constituent of Curcuma longa, has shown numerous biological and pharmacological activities, including antidiabetic effects. Here, a novel series of curcumin analogues were synthesized and evaluated for in vitro inhibition of aldose reductase (AR), the first and rate-limiting enzyme of the polyol pathway, which plays a key role in the onset and progression of diabetic complications. Biological activity studies showed that all the curcuminoids exhibited moderate to good AR inhibitory (ARI) activities compared with that of the quercetin standard. Importantly, compounds 8d, 8h, 9c, 9e, and 10g demonstrated promising ARI activities, with the 50% inhibitory concentration (IC50) values of 5.73, 5.95, 5.11, 5.78, and 5.10 µM, respectively. Four other compounds exhibited IC50 values in the range of 6.04–6.18 µM. Methyl and methoxy derivatives showed a remarkable ARI potential compared with that of other substitutions on the aromatic ring. Molecular docking experiments demonstrated that the most active curcuminoid (10g) was able to favorably bind in the active site of the AR enzyme. The potent ARI activities exhibited by the curcuminoids were attributed to their substitution patterns on the aromatic moiety, which may provide novel leads in the development of therapeutics for the treatment of diabetic complications.

scholarly journals Rhodanine-3-acetamide derivatives as aldose and aldehyde reductase inhibitors to treat diabetic complications: synthesis, biological evaluation, molecular docking and simulation studies

BMC Chemistry ◽  
2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Mohsinul Mulk Bacha ◽  
Humaira Nadeem ◽  
Sumera Zaib ◽  
Sadia Sarwar ◽  
Aqeel Imran ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Molecular Docking ◽  
Aldose Reductase ◽  
Diabetic Complications ◽  
Active Sites ◽  
Polyol Pathway ◽  
Biological Evaluation ◽  
Aldehyde Reductase ◽  
Standard Drug

AbstractIn diabetes, increased accumulation of sorbitol has been associated with diabetic complications through polyol pathway. Aldose reductase (AR) is one of the key factors involved in reduction of glucose to sorbitol, thereby its inhibition is important for the management of diabetic complications. In the present study, a series of seven 4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetamide derivatives 3(a–g) were synthesized by the reaction of 5-(4-hydroxy-3-methoxybenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetic acid (2a) and 5-(4-methoxybenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetic acid (2b) with different amines. The synthesized compounds 3(a–g) were investigated for their in vitro aldehyde reductase (ALR1) and aldose reductase (ALR2) enzyme inhibitory potential. Compound 3c, 3d, 3e, and 3f showed ALR1 inhibition at lower micromolar concentration whereas all the compounds were more active than the standard inhibitor valproic acid. Most of the compounds were active against ALR2 but compound 3a and 3f showed higher inhibition than the standard drug sulindac. Overall, the most potent compound against aldose reductase was 3f with an inhibitory concentration of 0.12 ± 0.01 µM. In vitro results showed that vanillin derivatives exhibited better activity against both aldehyde reductase and aldose reductase. The molecular docking studies were carried out to investigate the binding affinities of synthesized derivatives with both ALR1 and ALR2. The binding site analysis of potent compounds revealed similar interactions as were found by cognate ligands within the active sites of enzymes.

scholarly journals The Polyol Pathway as a Mechanism for Diabetic Retinopathy: Attractive, Elusive, and Resilient

2007 ◽  
Vol 2007 ◽  
pp. 1-10 ◽  
Author(s):  
Mara Lorenzi
Keyword(s):  
Diabetic Retinopathy ◽  
Aldose Reductase ◽  
Diabetic Complications ◽  
Polyol Pathway ◽  
New Drugs ◽  
Reductase Gene ◽  
Attractive Candidate ◽  
Rate Limiting ◽  
Intracellular Glucose

The polyol pathway is a two-step metabolic pathway in which glucose is reduced to sorbitol, which is then converted to fructose. It is one of the most attractive candidate mechanisms to explain, at least in part, the cellular toxicity of diabetic hyperglycemia because (i) it becomes active when intracellular glucose concentrations are elevated, (ii) the two enzymes are present in human tissues and organs that are sites of diabetic complications, and (iii) the products of the pathway and the altered balance of cofactors generate the types of cellular stress that occur at the sites of diabetic complications. Inhibition (or ablation) of aldose reductase, the first and rate-limiting enzyme in the pathway, reproducibly prevents diabetic retinopathy in diabetic rodent models, but the results of a major clinical trial have been disappointing. Since then, it has become evident that truly informative indicators of polyol pathway activity and/or inhibition are elusive, but are likely to be other than sorbitol levels if meant to predict accurately tissue consequences. The spectrum of abnormalities known to occur in human diabetic retinopathy has enlarged to include glial and neuronal abnormalities, which in experimental animals are mediated by the polyol pathway. The endothelial cells of human retinal vessels have been noted to have aldose reductase. Specific polymorphisms in the promoter region of the aldose reductase gene have been found associated with susceptibility or progression of diabetic retinopathy. This new knowledge has rekindled interest in a possible role of the polyol pathway in diabetic retinopathy and in methodological investigation that may prepare new clinical trials. Only new drugs that inhibit aldose reductase with higher efficacy and safety than older drugs will make possible to learn if the resilience of the polyol pathway means that it has a role in human diabetic retinopathy that should not have gone undiscovered.

Development of aldose reductase inhibitors for the treatment of inflammatory disorders and cancer: current drug design strategies and future directions

2020 ◽  
Vol 27 ◽  
Author(s):  
Himangshu Sonowal ◽  
Kota V Ramana
Keyword(s):  
Aldose Reductase ◽  
Diabetic Complications ◽  
Potential Role ◽  
Polyol Pathway ◽  
Design Strategies ◽  
Future Directions ◽  
Inflammatory Disorders ◽  
Reductase Inhibitors ◽  
Potential Use

: Aldose Reductase (AR) is an enzyme that converts glucose to sorbitol during the polyol pathway of glucose metabolism. AR has been shown to be involved in the development of secondary diabetic complications due to its involvement in causing osmotic stress as well as oxidative stress. Various AR inhibitors have been tested for their use to treat secondary diabetic complications such as retinopathy, neuropathy, and nephropathy in clinical studies. Recent studies also suggest the potential role of AR in mediating various inflammatory complications. Therefore, the studies on the development and potential use of AR inhibitors to treat inflammatory complications and cancer besides diabetes currently are on rising. Further, genetic mutagenesis studies, computer modeling, and molecular dynamics studies have helped design novel and potent AR inhibitors. This review discussed the potential new therapeutic use of AR inhibitors in targeting inflammatory disorders and cancer besides diabetic complications. Further, we summarized recent studies on how AR inhibitors have been designed and developed for therapeutic purposes in the last few decades.

scholarly journals Relationship between Aldose reductase and superoxide dismutase inhibition capacities of indole-based analogs of melatonin derivatives

2009 ◽  
Vol 61 (4) ◽  
pp. 675-681 ◽  
Author(s):  
N. Daş-Evcimen ◽  
Ö. Yildirim ◽  
S. Suzen
Keyword(s):  
Aldose Reductase ◽  
Diabetic Complications ◽  
Morphological Changes ◽  
Antioxidant Properties ◽  
Polyol Pathway ◽  
Antioxidant Enzyme Activity ◽  
Indole Derivatives ◽  
The Third ◽  
The Relationship

Aldose reductase (AR) has been implicated in the etiology of diabetic complications. Under diabetic conditions, the elevated vascular glucose level causes an increased flux through the polyol pathway, which induces functional and morphological changes associated with secondary diabetic complications such as cataract, neuropathy, and nephrop?athy. Oxidative stress, antioxidants, and the polyol pathway have recently been found to be linked in pathological states. A large number of structurally different compounds have been studied as potent in vitro AR inhibitors (ARIs). However, with few exceptions, these compounds did not show clinical benefit, and some even produced serious side effects. In view of the ARI activity of certain indole derivative compounds and antioxidant properties of melatonin, we investigated some indole-based analogs of melatonin derivatives. Antioxidant and ARI activity tests were applied to nine indole derivatives that are substituted at the third and fifth positions. Also, the relationship between ARI and antioxidant enzyme activity is discussed.

scholarly journals Antiparasitic Properties of Cardiovascular Agents against Human Intravascular Parasite Schistosoma mansoni

2021 ◽  
Vol 14 (7) ◽  
pp. 686
Author(s):  
Raquel Porto ◽  
Ana C. Mengarda ◽  
Rayssa A. Cajas ◽  
Maria C. Salvadori ◽  
Fernanda S. Teixeira ◽  
...  
Keyword(s):  
Schistosoma Mansoni ◽  
Screening Strategy ◽  
Early Infection ◽  
Global Public Health ◽  
Parasitic Worm ◽  
Electron Microscopy Analysis ◽  
Health Significance ◽  
Microscopy Analysis

The intravascular parasitic worm Schistosoma mansoni is a causative agent of schistosomiasis, a disease of great global public health significance. Praziquantel is the only drug available to treat schistosomiasis and there is an urgent demand for new anthelmintic agents. Adopting a phenotypic drug screening strategy, here, we evaluated the antiparasitic properties of 46 commercially available cardiovascular drugs against S. mansoni. From these screenings, we found that amiodarone, telmisartan, propafenone, methyldopa, and doxazosin affected the viability of schistosomes in vitro, with effective concentrations of 50% (EC50) and 90% (EC90) values ranging from 8 to 50 µM. These results were further supported by scanning electron microscopy analysis. Subsequently, the most effective drug (amiodarone) was further tested in a murine model of schistosomiasis for both early and chronic S. mansoni infections using a single oral dose of 400 mg/kg or 100 mg/kg daily for five consecutive days. Amiodarone had a low efficacy in chronic infection, with the worm and egg burden reduction ranging from 10 to 30%. In contrast, amiodarone caused a significant reduction in worm and egg burden in early infection (>50%). Comparatively, treatment with amiodarone is more effective in early infection than praziquantel, demonstrating the potential role of this cardiovascular drug as an antischistosomal agent.

scholarly journals Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 2867
Author(s):  
Lucia Kovacikova ◽  
Marta Soltesova Prnova ◽  
Magdalena Majekova ◽  
Andrej Bohac ◽  
Cimen Karasu ◽  
...  
Keyword(s):  
Aldose Reductase ◽  
Diabetic Complications ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Biological Activities ◽  
In Vivo Models ◽  
Aldose Reductase Inhibitors ◽  
Reductase Inhibitors ◽  
Promising Therapeutic Approach

Aldose reductase (AR, ALR2), the first enzyme of the polyol pathway, is implicated in the pathophysiology of diabetic complications. Aldose reductase inhibitors (ARIs) thus present a promising therapeutic approach to treat a wide array of diabetic complications. Moreover, a therapeutic potential of ARIs in the treatment of chronic inflammation-related pathologies and several genetic metabolic disorders has been recently indicated. Substituted indoles are an interesting group of compounds with a plethora of biological activities. This article reviews a series of indole-based bifunctional aldose reductase inhibitors/antioxidants (ARIs/AOs) developed during recent years. Experimental results obtained in in vitro, ex vivo, and in vivo models of diabetic complications are presented. Structure–activity relationships with respect to carboxymethyl pharmacophore regioisomerization and core scaffold modification are discussed along with the criteria of ‘drug-likeness”. Novel promising structures of putative multifunctional ARIs/AOs are designed.

scholarly journals Protective Pleiotropic Effect of Flavonoids on NAD+Levels in Endothelial Cells Exposed to High Glucose

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Daniëlle M. P. H. J. Boesten ◽  
Saskia N. I. von Ungern-Sternberg ◽  
Gertjan J. M. den Hartog ◽  
Aalt Bast
Keyword(s):  
Endothelial Cells ◽  
Enzyme Activity ◽  
Aldose Reductase ◽  
High Glucose ◽  
Umbilical Vein ◽  
Polyol Pathway ◽  
Pleiotropic Effect ◽  
Protective Role ◽  
Parp Activation

NAD+is important for oxidative metabolism by serving as an electron transporter. Hyperglycemia decreases NAD+levels by activation of the polyol pathway and by overactivation of poly(ADP-ribose)-polymerase (PARP). We examined the protective role of three structurally related flavonoids (rutin, quercetin, and flavone) during high glucose conditions in anin vitromodel using human umbilical vein endothelial cells (HUVECs). Additionally we assessed the ability of these flavonoids to inhibit aldose reductase enzyme activity. We have previously shown that flavonoids can inhibit PARP activation. Extending these studies, we here provide evidence that flavonoids are also able to protect endothelial cells against a high glucose induced decrease in NAD+. In addition, we established that flavonoids are able to inhibit aldose reductase, the key enzyme in the polyol pathway. We conclude that this protective effect of flavonoids on NAD+levels is a combination of the flavonoids ability to inhibit both PARP activation and aldose reductase enzyme activity. This study shows that flavonoids, by a combination of effects, maintain the redox state of the cell during hyperglycemia. This mode of action enables flavonoids to ameliorate diabetic complications.

scholarly journals From animal models to patients: the role of placental microRNAs, miR-210, miR-126, and miR-148a/152 in preeclampsia

2020 ◽  
Vol 134 (8) ◽  
pp. 1001-1025 ◽  
Author(s):  
Sonya Frazier ◽  
Martin W. McBride ◽  
Helen Mulvana ◽  
Delyth Graham
Keyword(s):  
Animal Models ◽  
Cell Types ◽  
Rodent Model ◽  
Hypertensive Disorder ◽  
Model Studies ◽  
Genetic Components ◽  
Immune Mediated ◽  
Hypertensive Disorder Of Pregnancy

Abstract Placental microRNAs (miRNAs) regulate the placental transcriptome and play a pathological role in preeclampsia (PE), a hypertensive disorder of pregnancy. Three PE rodent model studies explored the role of placental miRNAs, miR-210, miR-126, and miR-148/152 respectively, by examining expression of the miRNAs, their inducers, and potential gene targets. This review evaluates the role of miR-210, miR-126, and miR-148/152 in PE by comparing findings from the three rodent model studies with in vitro studies, other animal models, and preeclamptic patients to provide comprehensive insight into genetic components and pathological processes in the placenta contributing to PE. The majority of studies demonstrate miR-210 is upregulated in PE in part driven by HIF-1α and NF-κBp50, stimulated by hypoxia and/or immune-mediated processes. Elevated miR-210 may contribute to PE via inhibiting anti-inflammatory Th2-cytokines. Studies report an up- and downregulation of miR-126, arguably reflecting differences in expression between cell types and its multifunctional capacity. MiR-126 may play a pro-angiogenic role by mediating the PI3K-Akt pathway. Most studies report miR-148/152 family members are upregulated in PE. Evidence suggests they may inhibit DNA methylation of genes involved in metabolic and inflammatory pathways. Given the genetic heterogeneity of PE, it is unlikely that a single placental miRNA is a suitable therapeutic target for all patients. Investigating miRNAs in PE subtypes in patients and animal models may represent a more appropriate approach going forward. Developing methods for targeting placental miRNAs and specific placental cell types remains crucial for research seeking to target placental miRNAs as a novel treatment for PE.

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