Celastrol attenuates mitochondrial dysfunction and inflammation in palmitate-mediated insulin resistance in C3A hepatocytes

Bakar, Mohamad Hafizi Abu; Sarmidi, Mohamad Roji; Tan, Joo Shun; Rosdi, Mohamad Norisham Mohamad

doi:10.1016/j.ejphar.2017.01.043

Cited by 40 publications

(33 citation statements)

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“…Increasing evidence suggests that the overproduction of ROS may activate stress signals to the mitochondria and be important in a number of biological processes; this suggests that mitochondrial dysfunction, together with the impaired antioxidant system, may be involved in the pathophysiological mechanism and progression of PCOS-IR ( 29 , 30 ). There are two general pathways of apoptosis based on different apoptotic stimuli, termed the death receptor pathway and the mitochondrial-mediated pathway.…”

Section: Discussionmentioning

confidence: 99%

Mitochondria-targeted antioxidant therapy for an animal model of PCOS-IR

et al. 2018

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Polycystic ovary syndrome (PCOS) is a common endocrine disorder with unknown etiology and unsatisfactory clinical treatment. Considering the ethical limitations of studies involving humans, animal models that reflect features of PCOS and insulin resistance (IR) are crucial resources in investigating this syndrome. Our previous study showed that mitochondrial dysfunction resulted from pathogenic mutations of mitochondrial DNA (mtDNA), and that oxidative stress had an active role in the phenotypic manifestation of PCOS-IR. Therefore, it was hypothesized that limiting oxidative stress and mitochondrial damage may be useful and effective for the clinical treatment of PCOS-IR. For this purpose, the present study examined the therapeutic effects of the mitochondria-targeted antioxidant MitoQ10 for PCOS-IR. Furthermore, the histopathology was used to analysis the ovarian morphological changes. The endocrine and reproductive related parameters were analyzed by ELISA approach. A PCOS-IR model was successfully established by subcutaneous injection of rats with testosterone propionate and feeding a high-fat diet. The 30 female Sprague-Dawley rats were then divided into three groups, comprising a control (n=10), animal model (PCOS-IR, n=10) and MitoQ10 treatment (n=10) group. It was found that MitoQ10 significantly improved the IR condition and reversed the endocrine and reproductive conditions of PCOS. In addition, the impaired mitochondrial functions were improved following MitoQ10 administration. Notably, western blot results suggested that this antioxidant reduced the expression levels of apoptosis-related proteins cytochrome c and B-cell lymphoma-2 (Bcl-2)-associated X protein, whereas the anti-apoptotic protein Bcl-extra large was increased following MitoQ10 treatment. Taken together, the data indicated that the MitoQ10 may have a beneficial favorable therapeutic effect on animals with PCOS-IR, most likely via the protection of mitochondrial functions and regulation of programmed cell death-related proteins.

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Section: Discussionmentioning

confidence: 99%

Mitochondria-targeted antioxidant therapy for an animal model of PCOS-IR

et al. 2018

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“…It also ameliorates dextran sulfate sodium-induced colitis in caspase-1 -/- mice by inhibiting the activation of NLRP3 inflammasomes and the subsequent secretion of IL-1β ( Yu X. et al, 2017 ). Celastrol potentiates mitochondrial damage and inflammation in palmitate-induced insulin resistance in C3A hepatocytes ( Abu Bakar et al, 2017 ). Treatment with celastrol also inhibits acute liver inflammation through the Nur77-dependent pathway and activation of autophagy in LPS and D -galactosamine-induced inflammation in mice ( Greenhill, 2015 ).…”

Section: Pharmacological Activities Of Celastrolmentioning

confidence: 99%

A Mechanistic Overview of Triptolide and Celastrol, Natural Products from Tripterygium wilfordii Hook F

et al. 2018

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Triptolide and celastrol are predominantly active natural products isolated from the medicinal plant Tripterygium wilfordii Hook F. These compounds exhibit similar pharmacological activities, including anti-cancer, anti-inflammation, anti-obesity, and anti-diabetic activities. Triptolide and celastrol also provide neuroprotection and prevent cardiovascular and metabolic diseases. However, toxicity restricts the further development of triptolide and celastrol. In this review, we comprehensively review therapeutic targets and mechanisms of action, and translational study of triptolide and celastrol. We systemically discuss the structure-activity-relationship of triptolide, celastrol, and their derivatives. Furthermore, we propose the use of structural derivatives, targeted therapy, and combination treatment as possible solutions to reduce toxicity and increase therapeutic window of these potent natural products from T. wilfordii Hook F.

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“…Experimentally, the prolonged exposure of hepatocytes to palmitate induces oxidative stress and then tilts the balance in mitochondrial dynamics toward excessive mitochondrial fission. The resulted mitochondrial dysfunction contributes to the progression of lipotoxicity and insulin resistance …”

Section: Introductionmentioning

confidence: 99%

Attenuation of Palmitic Acid–Induced Lipotoxicity by Chlorogenic Acid through Activation of SIRT1 in Hepatocytes

Yang

Wei

Sheng

2019

Molecular Nutrition Food Res

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Scope: Saturated free fatty acids (FFAs) induce hepatocyte lipotoxicity, wherein oxidative stress-associated mitochondrial dysfunction is mechanistically involved. Chlorogenic acid (CGA), a potent antioxidant and anti-inflammatory compound, protects against high-fat-diet-induced oxidative stress and mitochondrial dysfunction in liver. This study investigates whether CGA protects against FFA-induced hepatocyte lipotoxicity via the regulation of mitochondrial fission/fusion and elucidates its underlying mechanisms. Methods and results: AML12 cell, a non-transformed hepatocyte cell line, is treated with palmitate. Here, it is shown that CGA prevents palmitate-induced lipotoxicity by activation of SIRT1 regulated mitochondrial morphology. CGA treatment mitigates oxidative stress and mitochondrial dysfunction, as evidenced by a decrease in reactive oxygen species (ROS) production, and an increase in mitochondrial mass and mitochondrial membrane potential. CGA also significantly decreases Bax expression and thereby reduces mitochondria-mediated caspase-dependent apoptosis. Mechanistically, CGA attenuates ROS-induced mitochondrial fragmentation by inhibiting dynamin-related protein 1 (Drp1) and enhancing Mfn2 expression. In contrast, the inhibitory effects of CGA on the generation of mitochondrial ROS and Drp1 are blocked by siRNA knockdown of SIRT1. Conclusion: Collectively, these findings show that supplementation with CGA protects hepatocytes from FFA-induced lipotoxicity through activation of SIRT1, which reverses the oxidative stress and dysfunction of mitochondrial biogenesis directly.

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Celastrol attenuates mitochondrial dysfunction and inflammation in palmitate-mediated insulin resistance in C3A hepatocytes

Cited by 40 publications

References 50 publications

Mitochondria-targeted antioxidant therapy for an animal model of PCOS-IR

Mitochondria-targeted antioxidant therapy for an animal model of PCOS-IR

A Mechanistic Overview of Triptolide and Celastrol, Natural Products from Tripterygium wilfordii Hook F

Attenuation of Palmitic Acid–Induced Lipotoxicity by Chlorogenic Acid through Activation of SIRT1 in Hepatocytes

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