Pharmacological evaluation of novel alagebrium analogs as methylglyoxal scavengers in vitro in cardiac myocytes and in vivo in SD rats

Dhar, Animesh; Udumula, Mary Priyanka; Medapi, Brahmam; Bhat, Audesh; Dhar, Indu; Malapati, Prasanthi; Babu, Mangali Suresh; Kalra, Jaspreet; Sriram, D.; Desai, Kaushik

doi:10.1016/j.ijcard.2016.08.243

Cited by 7 publications

(5 citation statements)

References 37 publications

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“…Optimization of existing compounds has been a particularly fruitful approach. Studies optimizing alagebrium or that resemble heterocyclic Schiff bases have yielded new drug leads that may overcome some of the challenges of existing compounds and function more effectively to remove AGEs [118,119]. Other promising approaches include bi-functional drugs, which can target multiple steps in AGE formation.…”

Section: Pharmaceutical Treatment Of Age Accumulationmentioning

confidence: 99%

Mechanistic targeting of advanced glycation end-products in age-related diseases

Rowan

Bejarano

Taylor

2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

167

125

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Glycative stress, caused by the accumulation of cytotoxic and irreversibly-formed sugar-derived advanced glycation end-products (AGEs), contributes to morbidity associated with aging, age-related diseases, and metabolic diseases. In this review, we summarize pathways leading to formation of AGEs, largely from sugars and glycolytic intermediates, and discuss detoxification of AGE precursors, including the glyoxalase system and DJ-1/Park7 deglycase. Disease pathogenesis downstream of AGE accumulation can be cell autonomous due to aggregation of glycated proteins and impaired protein function, which occurs in ocular cataracts. Extracellular AGEs also activate RAGE signaling, leading to oxidative stress, inflammation, and leukostasis in diabetic complications such as diabetic retinopathy. Pharmaceutical agents have been tested in animal models and clinically to diminish glycative burden. We summarize existing strategies and point out several new directions to diminish glycative stress including: plant-derived polyphenols as AGE inhibitors and glyoxalase inducers; improved dietary patterns, particularly Mediterranean and low glycemic diets; and enhancing proteolytic capacities of the ubiquitin-proteasome and autophagy pathways that are involved in cellular clearing of AGEs.

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Section: Pharmaceutical Treatment Of Age Accumulationmentioning

confidence: 99%

Mechanistic targeting of advanced glycation end-products in age-related diseases

Rowan

Bejarano

Taylor

2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

167

125

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“…H9C2 cells were seeded on glass cover slips, which were placed in a six-well plate and incubated with different substrates for 24 hours, and subjected to PKR, JNK, and caspase-3 staining. As described previously, 22 the treated cells were fixed with 4% paraformaldehyde for 15 minutes at room temperature and washed twice with 0.01 N phosphate buffered saline (PBS). The cells were permeabilized with 0.1% Triton X-100 for 5 minutes and three washes with PBS, the cells were incubated with 3% BSA (in PBST) for 1 hour to block nonspecific binding sites.…”

Section: Immunofluorescence Stainingmentioning

confidence: 99%

Inhibition of protein kinase R protects against palmitic acid–induced inflammation, oxidative stress, and apoptosis through the JNK/NF‐kB/NLRP3 pathway in cultured H9C2 cardiomyocytes

Mangali

Bhat

Udumula

et al. 2018

J of Cellular Biochemistry

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Background and Purpose: Double-stranded RNA-dependent protein kinase (PKR) is a critical regulator of apoptosis, oxidative stress, and inflammation under hyperlipidemic and insulin resistance conditions. Saturated free fatty acids, such as palmitic acid (PA), are known inducers of apoptosis in numerous cell types. However, the underlying molecular mechanism is not fully understood. The aim of the present study was to examine the effect of PA on cultured rat H9C2 cardiac myocytes cells and to investigate the PKR mediated harmful effects of PA in vitro in cultured cardiomyocytes.Experimental Approach: PKR expression was determined by immunofluorescence and immunoblotting. Oxidative stress and apoptosis were determined by flow cytometry and assay kits. The expression of different gene markers of apoptosis, oxidative stress, and inflammation were measured by Western blot analysis and reverse transcription polymerase chain reaction.Key Results: PKR expression, reactive oxygen species levels as well as apoptosis were increased in PA-treated cultured H9C2 cardiomyocytes. The harmful effects of PA were attenuated by a selective PKR inhibitor, C16.Moreover, we observed that upregulation of c-Jun N-terminal kinase (JNK), nuclear factor-kB (NF-kB) and NACHT, LRR and PYD domains-containing protein 3 (NLRP3) pathways is associated with increased expression of interleukin 6 and tumor necrosis factor-α in PA-treated cardiomyocytes and attenuation by a selective PKR inhibitor.Conclusion and Implications: Our study reports, for the first time, that PKRmediated harmful effects of PA in cultured cardiomyocytes via activation of

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“…In our homogenization schema, it is possible that in DMM, where the intracellular components are removed, the AGEs are in the pellet and thus are not measurable. To test this theory, we treated DMM with ALT-711, an AGE-specific cross-link breaker, and showed that there was no longer a reduction in hydroxyproline with age [97]. When we measured AGEs in the ALT-711 treated DMM, there was a reduction in the 1-month and 20-month samples compared to no treatment, showing that ALT-711 is effective in reducing elevated levels of AGEs.…”

Section: Discussionmentioning

confidence: 99%

Advanced Glycation End Products Are Retained in Decellularized Muscle Matrix Derived from Aged Skeletal Muscle

Olson

Nguyen

Heise

et al. 2021

IJMS

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Decellularized tissues are biocompatible materials that engraft well, but the age of their source has not been explored for clinical translation. Advanced glycation end products (AGEs) are chemical cross-links that accrue on skeletal muscle collagen in old age, stiffening the matrix and increasing inflammation. Whether decellularized biomaterials derived from aged muscle would suffer from increased AGE collagen cross-links is unknown. We characterized gastrocnemii of 1-, 2-, and 20-month-old C57BL/6J mice before and after decellularization to determine age-dependent changes to collagen stiffness and AGE cross-linking. Total and soluble collagen was measured to assess if age-dependent increases in collagen and cross-linking persisted in decellularized muscle matrix (DMM). Stiffness of aged DMM was determined using atomic force microscopy. AGE levels and the effect of an AGE cross-link breaker, ALT-711, were tested in DMM samples. Our results show that age-dependent increases in collagen amount, cross-linking, and general stiffness were observed in DMM. Notably, we measured increased AGE-specific cross-links within old muscle, and observed that old DMM retained AGE cross-links using ALT-711 to reduce AGE levels. In conclusion, deleterious age-dependent modifications to collagen are present in DMM from old muscle, implying that age matters when sourcing skeletal muscle extracellular matrix as a biomaterial.

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Pharmacological evaluation of novel alagebrium analogs as methylglyoxal scavengers in vitro in cardiac myocytes and in vivo in SD rats

Cited by 7 publications

References 37 publications

Mechanistic targeting of advanced glycation end-products in age-related diseases

Mechanistic targeting of advanced glycation end-products in age-related diseases

Inhibition of protein kinase R protects against palmitic acid–induced inflammation, oxidative stress, and apoptosis through the JNK/NF‐kB/NLRP3 pathway in cultured H9C2 cardiomyocytes

Advanced Glycation End Products Are Retained in Decellularized Muscle Matrix Derived from Aged Skeletal Muscle

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