Geranylgeraniol prevents statin-induced skeletal muscle fatigue without causing adverse effects in cardiac or vascular smooth muscle performance

Irwin, J.; Fenning, Andrew; Vella, Rebecca

doi:10.1016/j.trsl.2019.08.004

Cited by 11 publications

(9 citation statements)

References 71 publications

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“…Our study showed that GGOH could restore the impaired macrophage efferocytosis by ZA. GGOH also proves to increase cell viability and differentiation of osteoblast precursors, osteoclasts, and vascular smooth muscle cells under bisphosphonate treatment ( Zafar et al, 2016 ; Fliefel et al, 2019 ; Irwin et al, 2020 ). Taken together, these findings all imply GGOH as a potential target for BRONJ treatment.…”

Section: Discussionmentioning

confidence: 97%

Geranylgeraniol Restores Zoledronic Acid-Induced Efferocytosis Inhibition in Bisphosphonate-Related Osteonecrosis of the Jaw

Chen

Zhu

et al. 2021

Front. Cell Dev. Biol.

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Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe side effect of long-term administration of bisphosphonates such as zoledronic acid (ZA), but its pathogenesis remains unclear. Impairment of the clearance of apoptotic cells (termed “efferocytosis”) by ZA may be associated with the pathogenesis of BRONJ. The aim of this study was to investigate whether ZA might inhibit macrophage efferocytosis and promote osteocytic apoptosis, and the underlying mechanisms responsible for the disturbing balance between clean and generation of osteocytic apoptosis. We found that ZA significantly promoted the apoptosis of osteocyte and pre-osteoblast via BRONJ mouse models and in vitro MC3T3-E1 but also inhibited the efferocytosis of macrophage on apoptotic cells. Moreover, supplement with geranylgeraniol (GGOH), a substrate analog for geranylgeranylation of Rac1, could restore Rac1 homeostasis and rescue macrophage efferocytosis. GGOH partially inhibits MC3T3-E1 apoptosis induced by ZA via downregulation of Rac1/JNK pathway. We also examined the Rac1 distribution and activation conditions in bone marrow-derived macrophages (BMDMs) and MC3T3-E1 under ZA treatment, and we found that ZA impaired Rac1 migration to BMDM membrane, leading to round appearance with less pseudopodia and efferocytosis inhibition. Moreover, ZA simultaneously activated Rac1, causing overexpression of P-JNK and cleaved caspase 3 in MC3T3-E1. Finally, the systemic administration of GGOH decreased the osteocytic apoptosis and improved the bone healing of the extraction sockets in BRONJ mouse models. Taken together, our findings provided a new insight and experimental basis for the application of GGOH in the treatment of BRONJ.

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Section: Discussionmentioning

confidence: 97%

Geranylgeraniol Restores Zoledronic Acid-Induced Efferocytosis Inhibition in Bisphosphonate-Related Osteonecrosis of the Jaw

Chen

Zhu

et al. 2021

Front. Cell Dev. Biol.

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“…In turn, geranylgeraniol is an intermediate in the biosynthesis of cholesterol, and it is believed to regulate the activity of 3-hydroxy-3-methylglutaryl-CoA (HMG-Coa) reductase negatively. Both tocotrienols and geranylgeraniol are research subjects due to their biological activities, including cardioprotective and neuroprotective effects, hypolipidemic activity, metabolic disorder prevention, and antitumoral activity [10][11][12]. A fundamental approach in the process of drug discovery is pharmaceutical chemistry.…”

Section: Molecules' Structure Obtention and Biological Activity Predi...mentioning

confidence: 99%

“…Both tocotrienols and geranylgeraniol are research subjects due to their biological activities, including cardioprotective and neuroprotective effects, hypolipidemic activity, metabolic disorder prevention, and antitumoral activity [ 10 , 11 , 12 ]. A fundamental approach in the process of drug discovery is pharmaceutical chemistry.…”

Section: Introductionmentioning

confidence: 99%

Potential of the Compounds from Bixa orellana Purified Annatto Oil and Its Granules (Chronic®) against Dyslipidemia and Inflammatory Diseases: In Silico Studies with Geranylgeraniol and Tocotrienols

et al. 2022

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Some significant compounds present in annatto are geranylgeraniol and tocotrienols. These compounds have beneficial effects against hyperlipidemia and chronic diseases, where oxidative stress and inflammation are present, but the exact mechanism of action of such activities is still a subject of research. This study aimed to evaluate possible mechanisms of action that could be underlying the activities of these molecules. For this, in silico approaches such as ligand topology (PASS and SEA servers) and molecular docking with the software GOLD were used. Additionally, we screened some pharmacokinetic and toxicological parameters using the servers PreADMET, SwissADME, and ProTox-II. The results corroborate the antidyslipidemia and anti-inflammatory activities of geranylgeraniol and tocotrienols. Notably, some new mechanisms of action were predicted to be potentially underlying the activities of these compounds, including inhibition of squalene monooxygenase, lanosterol synthase, and phospholipase A2. These results give new insight into new mechanisms of action involved in these molecules from annatto and Chronic®.

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“…Moreover, these experiments revealed that different statins, depending on the degree of their lipophilicity, cause more (SIM, higher lipophilicity) or less (ATV, lower lipophilicity) myotoxicity manifested in impaired cellular mitochondrial respiration. Notably, studies conducted on a rodent model of statin-induced myalgia have also confirmed that the administration of GGOH can prevent skeletal muscle fatigue [ 91 ].…”

Section: Models For Study Of Lipid-lowering Drug-induced Myopathiesmentioning

confidence: 99%

Zebrafish as a Model for the Study of Lipid-Lowering Drug-Induced Myopathies

Dubińska–Magiera

Migocka-Patrzałek

Lewandowski

et al. 2021

IJMS

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Drug-induced myopathies are classified as acquired myopathies caused by exogenous factors. These pathological conditions develop in patients without muscle disease and are triggered by a variety of medicaments, including lipid-lowering drugs (LLDs) such as statins, fibrates, and ezetimibe. Here we summarise the current knowledge gained via studies conducted using various models, such as cell lines and mammalian models, and compare them with the results obtained in zebrafish (Danio rerio) studies. Zebrafish have proven to be an excellent research tool for studying dyslipidaemias as a model of these pathological conditions. This system enables in-vivo characterization of drug and gene candidates to further the understanding of disease aetiology and develop new therapeutic strategies. Our review also considers important environmental issues arising from the indiscriminate use of LLDs worldwide. The widespread use and importance of drugs such as statins and fibrates justify the need for the meticulous study of their mechanism of action and the side effects they cause.

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Geranylgeraniol prevents statin-induced skeletal muscle fatigue without causing adverse effects in cardiac or vascular smooth muscle performance

Cited by 11 publications

References 71 publications

Geranylgeraniol Restores Zoledronic Acid-Induced Efferocytosis Inhibition in Bisphosphonate-Related Osteonecrosis of the Jaw

Geranylgeraniol Restores Zoledronic Acid-Induced Efferocytosis Inhibition in Bisphosphonate-Related Osteonecrosis of the Jaw

Potential of the Compounds from Bixa orellana Purified Annatto Oil and Its Granules (Chronic®) against Dyslipidemia and Inflammatory Diseases: In Silico Studies with Geranylgeraniol and Tocotrienols

Zebrafish as a Model for the Study of Lipid-Lowering Drug-Induced Myopathies

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