LCZ696 Protects against Diabetic Cardiomyopathy-Induced Myocardial Inflammation, ER Stress, and Apoptosis through Inhibiting AGEs/NF-κB and PERK/CHOP Signaling Pathways

Belali, Osamah M; Ahmed, Mohammed M.; Mohany, Mohamed; Belali, Tareg M.; Alotaibi, Meshal M.; Alhoshani, Ali; Al-Rejaie, Salim S.

doi:10.3390/ijms23031288

Cited by 26 publications

(15 citation statements)

References 54 publications

(65 reference statements)

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“…Our study showed that the expression of eyeball AGEs in DM mice was also positively correlated with AGE levels in the serum and kidneys. This is similar to the results of previous studies (9).We also found that AGEs promoted renal pathological damage and podocyte injury in DKD mice through the NF-kB signaling pathway, which was consistent with the results of Coughlan MT et al (21,25). The characteristics of AGEs deposited in multiple tissues and cells in the present study are consistent with these findings from previous studies, which offers a partial explanation for the concept of "detection of AGEs through noninvasive lenses to reflect kidney damage".…”

Section: Discussionsupporting

confidence: 93%

“…AGEs contain substances with fluorescent properties, such as pentosidine and imidazoline. Thus, AGEs in the human body can be detected by special instruments without specific exogenous labeling.AF of the lens, skin tissue and serum can represent the blood glucose level in DM patients to a certain extent (23)(24)(25)(26)(27)(28).Lens AF measurement is a noninvasive and rapid method that can be readily used in doctors' offices that indirectly shows AGE accumulation in the natural lens of the eye, most commonly due to DM (28,29). The results of Frederick Cahn et al showed that lens autofluorescence levels were highly predictive of diabetes and that progressively higher fluorescence deviations were observed in prediabetes, type 2 diabetes, and type 1 diabetes (30).However, the adoption of noninvasive AGEs technology to detect and evaluate DKD has not been reported.…”

Section: Discussionmentioning

confidence: 99%

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Exploration of Noninvasive Detection of Advanced Glycation End Products in the Lens to Screen for Diabetic Kidney Disease

Zhang

Gao²,

Yang

et al. 2022

Front. Endocrinol.

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Diabetic kidney disease (DKD) is a complication of diabetes, which is the most common cause of end-stage renal disease (dialysis). DKD has a high mortality rate, and only early detection can nip this disease in the bud. Advanced glycation end products (AGEs)are generally believed to be involved in the occurrence of DKD. Studies have shown that the lens AGEs fluorescence for noninvasive detection has high consistency with the gold standard OGTT, has high sensitivity and specificity, and could be used as a practical tool for the early screening of type 2 diabetes mellitus (T2DM).Therefore, we speculated that the noninvasive lens AGEs fluorescence detection method can be used to predict the occurrence of DKD. This study detected levels of AGEs in multiple cellular and tissues and analyzed the relationships between AGEs and lens, eyeballs, peripheral blood mononuclear cell (PBMC), serum, and kidney. Additionally, we examined the possible role of lens AGEs fluorescence in DKD screening. Our preexperimental study found that lens AGE levels in patients with T2DM were positively correlated with PBM and serum AGE levels. Lens AGE levels in patients with T2DM were negatively correlated with eGFR and positively correlated with urinary ACR. The animal and cell experiments showed that the AGE levels in the eyeballs of DM mice were also positively correlated with those in the serum and kidney. To increase the reliability of the experiment, we increased the sample size. In our results, lens AGEs levels were positively correlated with the occurrence of DKD, and the incidence of DKD in the high lens AGEs group was 2.739 times that in the low lens AGEs group. The receiver operating characteristic (ROC) curves showed that patients with T2DM with a lens AGEs value ≥ 0.306 were likely to have DKD. The area under the ROC curve of the noninvasive technique for identifying DKD was 0.757 (95% Cl: 0.677-0.838, p<0.001), and the sensitivity and specificity were 70.0% and 78.7%, respectively. These results suggest that noninvasive lens AGEs detection technology has certain clinical value in diagnosing whether patients with T2DM have DKD.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Exploration of Noninvasive Detection of Advanced Glycation End Products in the Lens to Screen for Diabetic Kidney Disease

Zhang

Gao²,

Yang

et al. 2022

Front. Endocrinol.

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“…Dysfunctional mitochondria can cause increased ROS production and the release of factors that favor cell death, such as cytochrome C (an apoptosis-inducing factor) and Smac/DIABLO (the second activator of caspases) [21,74,81,82], and the induction of pyroptosis, characterized by activation of the inflammasome through the activation of caspase 1 and pro-inflammatory cytokines [83][84][85], although this sub-type of programmed cell death has previously been associated with infection by intracellular pathogens. Various ROS scavengers or antioxidants reduced cardiomyocyte death and attenuate diabetic heart injury in experimental animal models [81,86].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial-derived Peptide Single-nucleotide Polymorphisms Associated with Cardiovascular Complications in Type 2 Diabetes

Gaona¹,

Gregorio²,

Jiménez³

et al. 2022

Preprint

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Since the discovery of mitochondrial-derived peptides (MDP), their participation in cellular metabolism is no longer considered as the sole function of the mitochondria, but importance was also attached to its role as a source of protective factors of metabolic stress. These peptides are encoded in the mitochondrial genome and translated into the mitochondria or cytoplasm, to signal within the cell or be released and bind to membrane receptors. The objective of this work was explored and compare the frequency of MT-RNR1 and MT-RNR2 variants in sequences obtained from T2D individuals and control population. 213 different mitochondrial polymorphisms previously reported in the literature associated with T2D and cardiovascular diseases were analyzed. We can found three variants in the MT-RNR1 not related with MOTS-c coding sequence: m.1189T>C (rs28358571), m.1420T>C (rs111033356), and m.1438A>G (rs2001030); and secondly, three polymorphisms associated to MT-RNR2 m.2667T>C (rs878870626) related to humanin, m.1811A>G (rs28358576) in SHPL3 and m.3027T>C (rs199838004) in SHPL6 associated with statistical differences between the T2D and control group. All these findings were previously related to cardiovascular complications in literature and, as far as we know, relating for the first time in diabetic patients.

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“…Sacubitril/valsartan significantly downregulates advanced glycation end products formation and receptor for advanced glycation end-product (RAGE) expression while decreasing C/EBP homologous protein (CHOP) and phosphorylated PKR-like endoplasmic reticulum kinase (PERK) expression levels in rats with diabetic cardiomyopathy (DCM) ( 26 ). This leads to improved endoplasmic reticulum (ER) stress and DCM-induced apoptosis.…”

Section: Mechanisms Of Action Of Sacubitril Valsartan: Experimental E...mentioning

confidence: 99%

The history and mystery of sacubitril/valsartan: From clinical trial to the real world

Zhang

Zou

Wang

et al. 2023

Front. Cardiovasc. Med.

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Heart failure is a serious threat to human health, with morbidity and mortality rates increasing despite the existence of multiple treatment options. Therefore, it is necessary to identify new therapeutic targets for this disease. Sacubitril/valsartan is a supramolecular sodium salt complex of the enkephalinase inhibitor prodrug sacubitril and the angiotensin receptor blocker valsartan. Its combined action increases endogenous natriuretic peptides while inhibiting the renin-angiotensin-aldosterone system and exerting cardioprotective effects. Clinical evidence suggests that sacubitril/valsartan is superior to conventional renin-angiotensin-aldosterone inhibitor therapy for patients with reduced ejection fraction heart failure who can tolerate angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. The therapy reduces the risk of heart failure hospitalization, cardiovascular mortality, and all-cause mortality and has a better safety and tolerability record. This review describes the potential pathophysiological mechanisms of cardiomyocyte injury amelioration by sacubitril/valsartan. We explore the protective effects of sacubitril/valsartan and outline the therapeutic value in patients with heart failure by summarizing the results of recent large clinical trials. Furthermore, a preliminary outlook shows that sacubitril/valsartan may be effective at treating other diseases, and provides some exploratory observations that lay the foundation for future studies on this drug.

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LCZ696 Protects against Diabetic Cardiomyopathy-Induced Myocardial Inflammation, ER Stress, and Apoptosis through Inhibiting AGEs/NF-κB and PERK/CHOP Signaling Pathways

Cited by 26 publications

References 54 publications

Exploration of Noninvasive Detection of Advanced Glycation End Products in the Lens to Screen for Diabetic Kidney Disease

Exploration of Noninvasive Detection of Advanced Glycation End Products in the Lens to Screen for Diabetic Kidney Disease

Mitochondrial-derived Peptide Single-nucleotide Polymorphisms Associated with Cardiovascular Complications in Type 2 Diabetes

The history and mystery of sacubitril/valsartan: From clinical trial to the real world

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