AMPK allostery: A therapeutic target for the management/treatment of diabetic nephropathy

Ayinde, Kehinde Sulaimon; Olaoba, Olamide Tosin; Ibrahim, Boyenle; Du, Lei; Lü, Qian; Yin, Xiaoxing; Adelusi, Temitope Isaac

doi:10.1016/j.lfs.2020.118455

Cited by 21 publications

(16 citation statements)

References 197 publications

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“…The regulation of signaling pathways associated with various pathologies through the targeting of their key protein components could serve as molecular therapeutic targets for the management/treatment of various diseases [ 31 , 32 , 33 , 34 , 35 ]. In light of this, we used reported antioxidant compounds to target Nrf2 repressor (Keap1) using in silico methodologies in order to figure out the compounds with the best inhibitory potential against Keap1.…”

Section: Discussionmentioning

confidence: 99%

Molecular dynamics, quantum mechanics and docking studies of some Keap1 inhibitors – An insight into the atomistic mechanisms of their antioxidant potential

Adelusi

Abdul-Hammed

Idris

et al. 2021

Heliyon

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Inhibitors of Keap1 would disrupt the covalent interaction between Keap1 and Nrf2 to unleash Nrf2 transcriptional machinery that orchestrates its cellular antioxidant, cytoprotective and detoxification processes thereby, protecting the cells against oxidative stress mediated diseases. In this in silico research, we investigated the Keap1 inhibiting potential of fifty (50) antioxidants using pharmacokinetic ADMET profiling, bioactivity assessment, physicochemical studies, molecular docking investigation, molecular dynamics and Quantum mechanical-based Density Functional Theory (DFT) studies using Keap1 as the apoprotein control. Out of these 50 antioxidants, Maslinic acid (MASA), 18-alpha-glycyrrhetinic acid (18-AGA) and resveratrol stand out by passing the RO5 (Lipinski rule of 5) for the physicochemical properties and ADMET studies. These three compounds also show high binding affinity of -10.6 kJ/mol, -10.4 kJ/mol and -7.8 kJ/mol at the kelch pocket of Keap1 respectively. Analysis of the 20ns trajectories using RMSD, RMSF, ROG and h-bond parameters revealed the stability of these compounds after comparing them with Keap1 apoprotein. Furthermore, the electron donating and accepting potentials of these compounds was used to investigate their reactivity using Density Functional Theory (HOMO and LUMO) and it was revealed that resveratrol had the highest stability based on its low energy gap. Our results predict that the three compounds are potential drug candidates with domiciled therapeutic functions against oxidative stress-mediated diseases. However, resveratrol stands out as the compound with the best stability and therefore, could be the best candidate with the best therapeutic efficacy.

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Section: Discussionmentioning

confidence: 99%

Molecular dynamics, quantum mechanics and docking studies of some Keap1 inhibitors – An insight into the atomistic mechanisms of their antioxidant potential

Adelusi

Abdul-Hammed

Idris

et al. 2021

Heliyon

Self Cite

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“…[ 2–6 ] A growing body of evidence demonstrates that oxidative stress plays a major role in the pathogenesis of DN. [ 7–9 ] Glucose metabolism disorder in renal cells will increase the production of free radicals such as reactive oxygen species (ROS). Oxidative stress induced by ROS leads to DNA damage in mitochondria, which, in turn, causes mitochondrial dysfunction and produces more ROS.…”

Section: Introductionmentioning

confidence: 99%

“…[ 21–24 ] However, low AMPK had been reported in diabetic kidneys, where it is involved in diverse physiological and pathologic processes in DN, including ECM deposition in the kidney parenchyma, podocyte autophagy, diabetic renal hypertrophy, and glomerulosclerosis. [ 25–28 ] As a regulator of cellular energy, AMPK can relieve inflammation and oxidative stress and promote apoptosis of fibroblasts in DN. AMPK activates tuberous sclerosis complex protein‐2 (TSC‐2) involved in cell growth and autophagy, and peroxisome proliferator‐activated receptor‐γ coactivator 1α (PGC‐1α) that suppresses protein and cholesterol synthesis and stimulates mitochondrial biogenesis, followed by a reduction in the expression of downstream NF‐κB signaling and inhibition of the inflammatory response (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…[ 21 ] It has been recognized that ROS plays a critical role in renal fibrosis. [ 7–9 ] Enhanced ROS production leads to renal fibrosis by triggering multiple signaling pathways, including the ones involved in mesangial cell hypertrophy, renal tubular epithelial cell migration and transformation, and fibroblast proliferation/activation. [ 29–34 ] AMPK also reduces the overexpression of ROS by inhibiting nicotinamide adenine dinucleotide phosphate oxidase [ 35 ] or increases the expression of superoxide dismutase through the AMPK–FoxO pathway to improve the cellular redox state and reduce the effects of ROS on cells.…”

Section: Introductionmentioning

confidence: 99%

“…[ 29–34 ] AMPK also reduces the overexpression of ROS by inhibiting nicotinamide adenine dinucleotide phosphate oxidase [ 35 ] or increases the expression of superoxide dismutase through the AMPK–FoxO pathway to improve the cellular redox state and reduce the effects of ROS on cells. [ 7,9 ] In addition, AMPK can induce apoptosis of fibroblasts by activating apoptosis signal‐regulating kinase/c‐Jun N‐terminal kinase pathways, thereby improving the glomerular fibrosis state, which can be a new strategy for the management of DN. [ 36 ] Together, it is reasonable to see AMPK as a potential therapeutic target for DN.…”

Section: Introductionmentioning

confidence: 99%

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Design, synthesis, and biological evaluation of 1,2,4‐oxadiazole‐containing pyrazolo[3,4‐b]pyridinones as a new series of AMPKɑ1β1γ1 activators

Xiao

Peng

Zheng

et al. 2021

Archiv der Pharmazie

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Adenosine monophosphate‐activated protein kinase (AMPK) plays a key role in maintaining whole‐body homeostasis and has been regarded as a therapeutic target for the treatment of diabetic nephropathy (DN). Herein, a series of 1,2,4‐oxadiazole‐containing pyrazolo[3,4‐b]pyridinone derivatives is reported as AMPKɑ1β1γ1 activators. The in vitro biological assay demonstrated that compounds 12k (EC50[AMPKα1γ1β1] = 180 nM) and 13q (EC50[AMPKα1γ1β1] = 2 nM) displayed significant enzyme activation. Mechanism studies indicated that both compounds reduced the levels of reactive oxygen species in a rat kidney fibroblast cell line (NRK‐49F) stimulated by transforming growth factor‐β and induced early apoptosis of NRK‐49F cells at 10 μM. Molecular docking studies suggested that 13q exhibited critical hydrogen‐bond interactions with the critical amino acid residues Lys29, Lys31, Asn111, and Asp88 at the binding site of the AMPK protein. These results enrich the structure pool of AMPK activators and provide novel lead compounds for the subsequent development of compounds with a promising therapeutic potential against DN.

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Melatonin prevents diabetes‐induced nephropathy by modulating the AMPK/SIRT1 axis: Focus on autophagy and mitochondrial dysfunction

Jain

Sherkhane

Kalavala

et al. 2022

Cell Biology International

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Impaired nutrient sensing mechanisms such as AMPK/silent information regulator type 1 (SIRT1) axis and autophagy in renal cells upon chronic diabetic condition accelerate renal injury and upregulating these mechanisms has been reported to prevent renal damage. Melatonin, a neuroendocrine agent, also possess antioxidant and AMPK modulatory effect. In the current study, the protective effect of melatonin against diabetic renal injury was assessed in streptozotocin‐induced diabetic nephropathy model and in in vitro model of high‐glucose‐induced tubular injury. Melatonin (3 and 10 mg/kg) was administered for 28 days after 4 weeks of diabetes induction in Sprague–Dawley rats. For in vitro model, the NRK‐52E cells were co‐incubated with high glucose and melatonin (25 and 50 μM). Melatonin supplementation abrogated the diabetes‐induced renal injury and improved renal function in diabetic rats. Immunoblot analysis of renal tissue lysates revealed improved expression of AMPK, as well as upregulated the expression of nuclear factor erythroid 2‐related factor 2, SIRT1, PGC‐1α, TFAM and enhanced autophagy upon melatonin treatment in diabetic rats. Likewise, melatonin treatment in high glucose exposed NRK‐52E cells improved expression of AMPK, enhanced mitochondrial biogenesis and positively modulated autophagy. However, these effects were repressed upon inhibition of AMPK activity in NRK‐52E cells by treatment of Compound‐C, suggesting that the protective effects of melatonin were mainly mediated through activation of AMPK. These results suggest that melatonin might mediate the renoprotective effect by upregulating the AMPK/SIRT1 axis, enhancing the autophagy and mitochondrial health in DIabetic Nephropathy.

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AMPK allostery: A therapeutic target for the management/treatment of diabetic nephropathy

Cited by 21 publications

References 197 publications

Molecular dynamics, quantum mechanics and docking studies of some Keap1 inhibitors – An insight into the atomistic mechanisms of their antioxidant potential

Molecular dynamics, quantum mechanics and docking studies of some Keap1 inhibitors – An insight into the atomistic mechanisms of their antioxidant potential

Design, synthesis, and biological evaluation of 1,2,4‐oxadiazole‐containing pyrazolo[3,4‐b]pyridinones as a new series of AMPKɑ1β1γ1 activators

Melatonin prevents diabetes‐induced nephropathy by modulating the AMPK/SIRT1 axis: Focus on autophagy and mitochondrial dysfunction

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