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Recent Advancements of Curcumin Analogs and Curcumin Formulations in Context to Modern Pharmacotherapeutics Perspectives
Published in Debarshi Kar Mahapatra, Cristóbal Noé Aguilar, A. K. Haghi, Applied Pharmaceutical Practice and Nutraceuticals, 2021
Animeshchandra G. M. Haldar, Kanhaiya M. Dadure, Debarshi Kar Mahapatra
Kondhare et al.55 have developed novel aldose reductase inhibitors (ARIs) of therapeutic significance. The nanodispersion of curcumin THERACURMIN tested for better ARI activity and evaluated the product for aldose reductase inhibition. Aldose Reductase, the key enzyme involved in the first and rate-limiting step of polyol pathway has been implicated in the development of late microvascular complications such as nerve-damaging due to diabetic, cataract, nephropathy, etc. As a consequence, the inhibition of this enzyme is of therapeutic significance to reduce the seriousness of chronic diabetic complications. It is evident from studies that THERACURMIN as expected exhibited excellent ARI activity in 20–30 μM range with IC50 of 3 μM. This is remarkable as the product contains only 15% curcuminoids in the total dispersion and curcumin itself displays potent aldose reductase inhibition activity.
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The polyol pathway enzyme aldose reductase (for an overview on docking studies with aldose reductase inhibitors see Zeyad et al., 2016) is implicated in diabetic complications. In the case of hyperglycemia glucose becomes reduced by aldose reductase at the expense of NADPH to sorbitol that subsequently is converted to fructose in presence of NAD+. The resulting shortage of NADPH and NAD+ leads among others to diminished glutathione levels associated with enhanced occurrence of oxidative stress and inflammatory processes, e.g., in eyes (retinopathy), heart (cardiovascular disease), kidney (nephropathy), and nerves and feet (neuropathy). The tripeptide glutathione (cysteine, glutamic acid, and glycine) is present in most mammalian tissue and acts as an antioxidant, a free radical scavenger and a detoxifying agent. The relation between cancer as well as other chronic diseases and oxidative stress relies on the fact that oxidative stress activates transcription factors (NF-κB, AP-1, p53, HIF-1α, PPAR-γ, β-catenin/Wnt, Nrf2, MAFK, etc.) leading to the expression of several hundred genes encoding growth factors, inflammatory cytokines, chemokines, cell cycle regulatory molecules, and anti-inflammatory molecules (Reuter et al., 2010; Sosa et al., 2013; Okita et al., 2017).
Diabetes and the Microcirculation
Published in John H. Barker, Gary L. Anderson, Michael D. Menger, Clinically Applied Microcirculation Research, 2019
Lastly, increased activity of the enzymes of the polyol pathway as a consequence of hyperglycemia may alter cellular functions due to the osmotic effects of increased sorbitol concentrations, depletion of myoinositol, or altered sodium-potassium ATPase activity.39 Increased polyol pathway activity is thought to be especially important in the pathogenesis of diabetic neuropathy, although it is also implicated in damage to other cell types, e.g., retinal pericytes.
Advances in oxidative stress in pathogenesis of diabetic kidney disease and efficacy of TCM intervention
Published in Renal Failure, 2023
Xiaoju Ma, Jingru Ma, Tian Leng, Zhongzhu Yuan, Tingting Hu, Qiuyan Liu, Tao Shen
Polyol pathway is one of the metabolic pathways [5] from glucose reduced to sorbitol under the actions of aldose reductase (AR) and nicotinamide adenine dinucleotide phosphate (NADPH) and subsequently oxidized to fructose in presence of sorbitol dehydrogenase (SDH) and nicotinamide adenine dinucleotide (NAD). In states of hyperglycemia, AR is activated, leading to increased production of sorbitol. Due to the consistent SDH activity, the produced sorbitols are accumulated in cells, which causes an increase in cell membrane permeability, resulting in exudation of intracellular matters such as inositol and reduced glutathione (GSH) and eventually oxidative stress response [6]. During this metabolic process, the activation of AR is dependent on NADPH, while the metabolism of excessive glucose consumes large amounts of NADPH, leading to reduced GSH production [7] and ROS scavenging capacity, eventually resulting in redox balance disorder in vivo. In the meantime, SDH-induced nicotinamide adenine dinucleotide (NADH) increases and then is oxidized to superoxides and other ROS under respiratory chain functions in mitochondria [8]. The accumulation of end product fructose can also induce oxidative stress and subsequent oxidative damage to tissue. Research revealed that AR inhibitor could reduce oxidative stress in the kidney to protect kidney function, which suggested that polyol induces DKD onset through inducing oxidative stress responses [9].
Development of new thiazolidine-2,4-dione hybrids as aldose reductase inhibitors endowed with antihyperglycaemic activity: design, synthesis, biological investigations, and in silico insights
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Abdelrahman Hamdi, Muhammad Yaseen, Wafaa A. Ewes, Mashooq Ahmad Bhat, Noha I. Ziedan, Hamed W. El-Shafey, Ahmed A. B. Mohamed, Mohamed R. Elnagar, Abdullah Haikal, Dina I. A. Othman, Abdullah A. Elgazar, Ahmed H. A. Abusabaa, Kamal S. Abdelrahman, Osama M. Soltan, Mostafa M. Elbadawi
Under hyperglycaemic state, higher than 30% of the BG is bio-transformed into sorbitol by aldose reductase (AR) enzyme resulting in the major diabetic secondary complications7–11. Subsequently, sorbitol dehydrogenase converts sorbitol to fructose through polyol pathway, which is a necessary mechanism for regulation of glucose metabolism in mammalian cells. AR is a key enzyme that belongs to aldo-keto reductase super-family involved in the polyol pathway for glucose reduction to sorbitol (Figure 1). It is believed that activation of this metabolic pathway is associated with the chronic diabetic complications like retinopathy, diabetic cataract, neuropathy, and nephropathy. Therefore, aldose reductase inhibitors (ARIs) emerged as a fruitful therapeutic tool to prevent the development of these metabolic complications via inhibition of the first step of polyol pathway1,7,8. ARIs have been found to supress and prevent sorbitol accumulation in specific tissues such as peripheral nerves, lens, and kidney. Accordingly, the decreased sorbitol flux by ARIs could be exploited as emerging approach for the management of major diabetes complications. Furthermore, the pathogenesis of sorbitol-induced diabetic complications may be result from interruption in cellular redox, sorbitol-osmotic effects, free radical defence, in addition to elevated oxidative and glycation stress1.
Models of enzyme inhibition and apparent dissociation constants from kinetic analysis to study the differential inhibition of aldose reductase
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Francesco Balestri, Mario Cappiello, Roberta Moschini, Umberto Mura, Antonella Del-Corso
The present study deals with aldose reductase (E.C. 1.1.1.21; AKR1B1), a NADPH-dependent reductase that, since its ability to transform glucose within the polyol pathway, is involved in the onset of a number of pathological states linked to hyperglycaemic conditions2. Thus, this enzyme is subjected to an intense investigation aiming to inhibit its activity. Since AKR1B1 is also able to reduce lipid peroxidation derived cytotoxic aldehydes, such as 4-hydroxy-2-nonenal (HNE), the inhibition of the enzyme may be causative of a lack or an impairment of its detoxification action. A new strategy (the “differential inhibition” approach) to inhibit the enzyme activity when acting on glucose reduction without affecting or with a limited effect on HNE reduction has been proposed3. Generally talking, the term “differential inhibition” may apply to multispecific enzymes and refers to the inhibition of the enzymatic action on one or more specific substrates, while the transformation of other substrates remains unaffected or affected to a reduced extent4.