A new strategy for osteoarthritis therapy: Inhibition of glycolysis

Tan, Chunmei; Li, Lanqing; Han, Juanjuan; Xu, Kang; Liu, Xianqiong

doi:10.3389/fphar.2022.1057229

Cited by 24 publications

(20 citation statements)

References 117 publications

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“…However, there are few reports on using serum PKM2 as a biomarker for disease diagnosis. [27][28][29][30] In this study, multivariate regression analysis showed that PKM2 and PCT were independent risk factors for sepsis in ICU patients; the ROC curve analysis showed that the AUC of PKM2 in diagnosing sepsis alone was 0.9154, with a high diagnostic value. Given the limitations of a single indicator, we combined PKM2 with PCT for the diagnosis of sepsis, achieving the highest clinical diagnostic value.…”

Section: Discussionmentioning

confidence: 52%

Changes of Serum Pyruvate Kinase M2 Level in Patients with Sepsis and Its Clinical Value

Wang,

Tang,

Zhang

2023

IDR

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The glucose metabolic reprogramming is an important pathological mechanism in sepsis, which involves a series of enzymes including Pyruvate kinase M2 (PKM2). The purpose of this study is to explore the diagnostic and prognostic value of serum PKM2 in sepsis patients. Patients and Methods: This study recruited 143 sepsis patients, 91 non-sepsis patients, and 65 physical examiners, divided into sepsis group, non-sepsis group, and control group. Measure the serum PKM2 concentration of subjects, collect and analyze clinical and laboratory indicators of all subjects. Independent risk factors were selected by Logistic regression analysis. The area under curve (AUC) was calculated by plotting the receiver operating characteristic (ROC) curve to determine the diagnostic and prognostic value of biomarkers. Results: Compared with non-sepsis and control groups, the serum PKM2 levels in the sepsis group were significantly increased (both P<0.001). PKM2 was an independent risk factor for sepsis and had the best diagnostic efficacy when combined with procalcitonin, with the AUC value of 0.9352. Patients with high levels of PKM2 were more likely to experience organ damage and had a higher incidence of septic shock. On the 1st and 3rd days of admission, the serum PKM2 levels in the septic shock group were higher than those in the sepsis group (both P<0.05), with AUC values of 0.7296 and 0.6247, respectively. On the 3rd and 7th days of admission, the serum PKM2 levels in the non-survival group were significantly higher than those in the survival group (both P<0.001), with AUC values of 0.7033 and 0.8732, respectively. Conclusion:The serum PKM2 levels in sepsis patients are significantly increased and correlated with disease severity and clinical outcomes. PKM2 may be a new diagnostic and prognostic biomarker for sepsis.

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Section: Discussionmentioning

confidence: 52%

Changes of Serum Pyruvate Kinase M2 Level in Patients with Sepsis and Its Clinical Value

Wang,

Tang,

Zhang

2023

IDR

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“…Studies have shown that under physiological conditions, most cells typically metabolize products through oxidative phosphorylation, but under pathological conditions, injured cells undergo a metabolic reprogramming changing from oxidative phosphorylation to aerobic glycolysis (Xie et al, 2022). Studies have shown that glycolysis plays an essential regulatory role in inflammatory diseases such as sepsis (Corcoran & O'Neill, 2016) and osteoarthritis (Arra et al, 2020; Tan et al, 2022). Our early research also found that valve calcification is accompanied by a high concentration of lipid and glycolysis metabolites (Wang, Huang, et al, 2021; Xie et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…Inhibiting the production of lactic acid significantly prevents this process. Recent studies have shown that, in addition to metabolic functions, the protein PTM function of lactic acid, that is, lactylation, is an important way for lactic acid to exert cellular functions such as regulating inflammation (Pan et al, 2022; Tan et al, 2022; Wang, Wang, et al, 2022; Wang, Yang, et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Andrographolide regulates H3 histone lactylation by interfering with p300 to alleviate aortic valve calcification

Wang,

Wang

et al. 2024

British J Pharmacology

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Background and PurposeOur previous studies have found that andrographolide (AGP) alleviates calcific aortic valve disease (CAVD), but the underlying mechanism is unclear. This study explores the molecular target and signal mechanisms of AGP in inhibiting CAVD.Experimental ApproachThe anti‐calcification effects of the aortic valve with AGP treatment were evaluated by alizarin red staining in vitro and ultrasound and histopathological assessment of a high‐fat (HF)‐fed ApoE−/− mouse valve calcification model. A correlation between the H3 histone lactylation (H3Kla) and calcification was detected. Molecular docking and surface plasmon resonance (SPR) experiments were further used to confirm p300 as a target for AGP. Overexpression (oe) and silencing (si) of p300 were used to verify the inhibitory effect of AGP targeting p300 on the H3Kla in vitro and ex vivo.Key ResultsAGP significantly inhibited calcium deposition in valve interstitial cells (VICs) and ameliorated aortic valve calcification. The multi‐omics analysis revealed the glycolysis pathway involved in CAVD, indicating that AGP interfered with lactate production by regulating lactate dehydrogenase A (LDHA). In addition, lactylation, a new post‐translational modification, was shown to have a role in promoting aortic valve calcification. Furthermore, H3Kla and H3K9la site were shown to correlate with Runx2 expression inhibition by AGP treatment. Importantly, we found that p300 transferase was the molecular target of AGP in inhibiting H3Kla.Conclusions and ImplicationsOur findings, for the first time, demonstrated that AGP alleviates calcification by interfering with H3Kla via p300, which might be a powerful drug to prevent CAVD.

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“…Conversely, ruminal fermentative disorders lead to the excessive accumulation of D-lactate, disrupting normal metabolic processes and causing pathological effects such as polysynovitis [ 1 , 5 ]. The presence of lactate within the joint during arthritis progression is considered a pivotal indicator linked to the inflammatory cascade, currently emerging as a promising target for the advancement of novel therapeutic interventions [ 3 , 41 , 42 ]. Lactate induces the release of Neutrophil Extracellular Traps (NETs) [ 43 ] and activates the secretion of pro-inflammatory cytokines in FLS [ 15 , 17 ], thereby contributing to the inflammation observed in arthritis.…”

Section: Discussionmentioning

confidence: 99%

“…The inhibition of the PI3K/Akt, NF-κB, and HIF-1α pathways may be intricately linked to the potential restoration of glycolytic reprogramming in FLSs [ 46 , 64 ]. Addressing both the inflammatory cascade and metabolic changes during arthritis represents an emerging scientific approach to alleviate joint inflammation [ 41 , 42 ]. Andrographolide, by modulating diverse cellular pathways such as PI3K/Akt, NF-κB, and HIF-1 [ 29 , 65 , 66 ], could exhibit an enhanced anti-inflammatory efficacy due to its multitarget effects on cellular metabolism [ 67 ].…”

Section: Discussionmentioning

confidence: 99%

Andrographolide Ameliorates Inflammatory Changes Induced by D-Lactate in Bovine Fibroblast-like Synoviocytes

Teuber,

Manosalva,

Alarcón

et al. 2024

Animals

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During acute ruminal acidosis, the manifestation of aseptic polysynovitis and lameness in cattle has been observed. Evidence suggests that joint inflammation can be attributed to the metabolic alterations induced by D-lactate in fibroblast-like synoviocytes (FLSs). We aimed to investigate whether andrographolide could mitigate the inflammation and metabolic alterations induced by D-lactate in bovine fibroblast-like synoviocytes (bFLSs). To assess this, bFLSs were cultured in the presence or absence of andrographolide. We evaluated its potential interference with the expression of proinflammatory cytokines, COX-2, HIF-1α, and LDHA using RT-qPCR. Furthermore, we investigated its potential interference with PI3K/Akt signaling and IκBα degradation through immunoblotting and flow cytometry, respectively. Our observations revealed that andrographolide reduced the elevation of IL-6, IL-8, COX-2, HIF-1α, and LDHA induced by D-lactate. Additionally, andrographolide demonstrated interference with the PI3K/Akt and NF-κB pathways in bFLSs. In conclusion, our findings suggest that andrographolide can potentially reverse the inflammatory effects and metabolic changes induced by D-lactate in bFLSs, showing promise as a therapeutic intervention for managing these conditions associated with lameness.

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A new strategy for osteoarthritis therapy: Inhibition of glycolysis

Cited by 24 publications

References 117 publications

Changes of Serum Pyruvate Kinase M2 Level in Patients with Sepsis and Its Clinical Value

Changes of Serum Pyruvate Kinase M2 Level in Patients with Sepsis and Its Clinical Value

Andrographolide regulates H3 histone lactylation by interfering with p300 to alleviate aortic valve calcification

Andrographolide Ameliorates Inflammatory Changes Induced by D-Lactate in Bovine Fibroblast-like Synoviocytes

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