The Function of PPARγ/AMPK/SIRT-1 Pathway in Inflammatory Response of Human Articular Chondrocytes Stimulated by Advanced Glycation End Products

Huang, Hao; Wang, Zhaojun; Zhang, Haibin; Liang, Jian-Xia; Cao, Wen-Dong; Wu, Qi; He, Chao-Peng; Chen, Cheng

doi:10.1248/bpb.b19-00036

Cited by 11 publications

(17 citation statements)

References 54 publications

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“…In addition, we have demonstrated that AGEs could downregulate the expression of PPARγ in the chondrocyte [27]. Recently, there a public study demonstrated that pioglitazone, as an elective PPARγ agonist, could restore the activity of AMPKα and SIRT1 inhibited by AGEs [28]. Thus, there need much more studies to identify the precise mechanism about how AGEs modulates AMPKα activity in chondrocyte.…”

Section: Discussionmentioning

confidence: 99%

Advanced Glycation End Products Induced Mitochondrial Dysfunction of Chondrocytes through Repression of AMPKα-SIRT1-PGC-1α Pathway

Yang¹,

Shi

Jin

et al. 2022

Pharmacology

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Introduction: Our previous studies have demonstrated advanced glycation end products (AGEs) was an important mediator in osteoarthritis (OA) which may induce mitochondrial dysfunction. AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and its downstream target peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) are the critical sensors that regulate mitochondrial biogenesis and have been recognized as therapeutic targets in OA. This study was designed to test whether AGEs caused mitochondrial dysfunction through modulation of AMPKα/SIRT1/PGC-1α. Methods: We knocked down or overexpressed AMPKα, SIRT1, and PGC-1α by small interfering RNA or plasmid DNA transfection, respectively. Mitochondrial membrane potential (△Ψ) was detected by tetraethylbenzimidazolyl carbocyanine iodide (JC-1) fluorescence probe. Results: The results showed that AGEs impaired △Ψ, intracellular ATP level, and mitochondrial DNA content, linked to decreased AMPKα, SIRT1, and PGC-1α expression in chondrocyte. AMPKα pharmacologic activation or overexpression of AMPKα, SIRT1, and PGC-1α reversed impairments of mitochondrial biogenesis, oxidative stress, and inflammation in AGEs-induced chondrocytes. However, AMPKα activation using AICAR had decreased capacity to increase each of those same effect readouts in AGEs-treated SIRT1-siRNA or PGC-1α-siRNA chondrocyte. Conclusion: Taken together, AGEs reduced the AMPKα/SIRT1/PGC-1α signaling in chondrocytes, leading to mitochondrial dysfunction as a result of increased oxidative stress, inflammation, and apoptosis. These results indicated that target AMPK may be as a novel therapeutic strategy for AGEs-related OA prevention.

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Section: Discussionmentioning

confidence: 99%

Advanced Glycation End Products Induced Mitochondrial Dysfunction of Chondrocytes through Repression of AMPKα-SIRT1-PGC-1α Pathway

Yang¹,

Shi

Jin

et al. 2022

Pharmacology

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“…AMPK is a fuel-sensing enzyme activated by a decrease in the cell's energy state to inhibit anabolic processes and to increase catabolic processes with the aim of restoring ATP reserves [43,[47][48][49][50]. Recent work suggests a relationship between SIRT1/AMPK, the inflammatory processes and OA, underlining how their activation could be crucial in this context and potentially protective against OA [50][51][52][53][54] This study investigated the effect of a bio-optimized curcumin on the genetic (SIRT1 and AMPK) and metabolic regulation of inflammation and associated symptomatology in patients with OA.…”

Section: Discussionmentioning

confidence: 99%

Bio-Optimized Curcuma as Adjuvant Therapy of Osteoarthritis and Its Influence on Gene Regulation (Sirt1), Metabolic Inflammation and Associated Symptoms

Bianchi¹,

Salamone²,

Vanheule³

et al. 2021

JNFP

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Background and aim: Osteoarthritis (OA) is a chronic degenerative disease characterized by an inflammatory state and significant oxidative stress. As curcuma is known for its anti-inflammatory and antioxidant activities, it could be used as alternative therapy next to or together with the standard treatment. This treatment consists of analgesics, steroids or non-steroidal anti-inflammatory drugs (NSAIDs) to reduce pain and inflammation related symptoms. The current study investigates the effect of bio-optimized curcuma on genetic (SIRT1) and metabolic regulation of inflammation and associated symptomatology in patients with osteoarthritis. Materials and methods: In the in vitro study, Hela human cells were seeded in 12-well plates, incubated with curcuma at different concentrations and incubated for 3, 6 and 24 hours. The targeted protein expression/phosphorylation was evaluated by immunoblotting, while cytotoxicity tests were performed by CellTiter-Blue Cell Viability Assay. In the in vivo study, a total of 33 patients were recruited and divided into 3 subgroups based on the treatment: standard treatment (ST), ST + curcuma and ST + curcuma + Vitamin D (2000UI). The health status (SF36) and osteoarthritis index (WOMAC score) were analyzed at 0; 1,5 and 3 months with blood sampling at 0 and 3 months for the evaluation of inflammation markers, 25 (OH) VitD and SIRT1. Results: in vitro data showed no statistically significant decrease (p>0.05) in the number of viable cells. The expression of SIRT1 and the activation of AMP activated protein kinase (AMPK) were significantly increased in all experimental groups compared with the control group (p<0.001). A significant increase in 25(OH) VitD values in the ST + curcuma + VitD group (p <0.007) and in SIRT1 in all groups taking curcuma (p <0.001) was shown. Also for IL-1 (p=0.031), IL-6 (p=0.031) and IFN-γ (p=0.013), all groups taking curcuma showed significantly lower inflammatory markers with no added value of vitamin D. Conclusions: Curcuma as an adjuvant to ST leads to a positive modulation of the SIRT1 pathway, a significant decline of blood inflammatory markers and a better osteoarthritis outcome. Osteoarthritis, a chronic degenerative disease characterized by an inflammatory state and significant oxidative stress Curcuma as alternative therapy next to or together with the standard treatment Effect of bio-optimized curcuma on genetic and metabolic regulation of inflammation Positive modulation of SIRT1 pathway, decline of blood inflammatory markers and a better OA outcome

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“…Glycation is a concentration-dependent process that is enhanced in diabetes and aging and was observed in OA [55]. AGE-related inhibition of ATP production and AMP-activated protein kinase (AMPK) phosphorylation [56] further point to high ATP concentrations in OA chondrocytes. In addition, AGEs can induce transcription factor nuclear factor kappa-lightchain-enhancer of activated B cells (NF-κB) and stress kinase ERK1/2 expression through the activation of the recognition receptor RAGE, followed by NOD-like receptor (NLR) family member NLRP3 inflammasome formation, and IL-1 receptor activation and thereby systemic inflammation [57].…”

Section: 43mentioning

confidence: 99%

Insulin Resistance in Osteoarthritis: Similar Mechanisms to Type 2 Diabetes Mellitus

Tchetina

Шарапова

2020

Journal of Nutrition and Metabolism

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Osteoarthritis (OA) and type 2 diabetes mellitus (T2D) are two of the most widespread chronic diseases. OA and T2D have common epidemiologic traits, are considered heterogenic multifactorial pathologies that develop through the interaction of genetic and environmental factors, and have common risk factors. In addition, both of these diseases often manifest in a single patient. Despite differences in clinical manifestations, both diseases are characterized by disturbances in cellular metabolism and by an insulin-resistant state primarily associated with the production and utilization of energy. However, currently, the primary cause of OA development and progression is not clear. In addition, although OA is manifested as a joint disease, evidence has accumulated that it affects the whole body. As pathological insulin resistance is viewed as a driving force of T2D development, now, we present evidence that the molecular and cellular metabolic disturbances associated with OA are linked to an insulin-resistant state similar to T2D. Moreover, the alterations in cellular energy requirements associated with insulin resistance could affect many metabolic changes in the body that eventually result in pathology and could serve as a unified mechanism that also functions in many metabolic diseases. However, these issues have not been comprehensively described. Therefore, here, we discuss the basic molecular mechanisms underlying the pathological processes associated with the development of insulin resistance; the major inducers, regulators, and metabolic consequences of insulin resistance; and instruments for controlling insulin resistance as a new approach to therapy.

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The Function of PPARγ/AMPK/SIRT-1 Pathway in Inflammatory Response of Human Articular Chondrocytes Stimulated by Advanced Glycation End Products

Cited by 11 publications

References 54 publications

Advanced Glycation End Products Induced Mitochondrial Dysfunction of Chondrocytes through Repression of AMPKα-SIRT1-PGC-1α Pathway

Advanced Glycation End Products Induced Mitochondrial Dysfunction of Chondrocytes through Repression of AMPKα-SIRT1-PGC-1α Pathway

Bio-Optimized Curcuma as Adjuvant Therapy of Osteoarthritis and Its Influence on Gene Regulation (Sirt1), Metabolic Inflammation and Associated Symptoms

Insulin Resistance in Osteoarthritis: Similar Mechanisms to Type 2 Diabetes Mellitus

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