Mitochondrial inhibitor as a new class of insulin sensitizer

Zhang, Yong; Ye, Jianping

doi:10.1016/j.apsb.2012.06.010

Cited by 45 publications

(46 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A). To further confirm these data, we studied in C28/I2 chondrocytes the phosphorylation profile of the Adenosine 5′ monophosphate‐activated protein kinase (AMPK), a regulator of cellular energy homeostasis usually activated upon mitochondrial failure . As shown in Figure B, AEA stimulation elicited an early activation of AMPK that was sustained up to 120 min.…”

Section: Resultsmentioning

confidence: 80%

Endogenous cannabinoid anandamide impairs cell growth and induces apoptosis in chondrocytes

et al. 2014

View full text Add to dashboard Cite

Endocannabinoids has been described to be involved in articular degenerative disease by modulating nociception and immune system. However, the role of the endocannabinoid anandamide on chondrocyte cell viability is still unclear. Therefore, we decided to study anandamide's effects on chondrocytes viability and to evaluate its interactions with the catabolic factor TNF (tumor necrosis factor). Chondrocyte vitality was evaluated by MTT assay. We investigated LDH release, chromatin condensation, cleavage of focal adhesion kinase (FAK), and caspases-3, 8, and 9 activation. c-MYC mRNA levels were determined by RT-PCR. We studied by Western blot the activation patterns of AKT, AMPK, ERK, p38, and JNK kinases. Finally, we evaluate the effect of anandamide in TNF-induced caspase-3 cleavage. Anandamide decreased chondrocyte vitality independently of its receptors. It induced AMPK activation without LDH release. Anandamide induced chromatin condensation, activation of caspase-3, 8, and 9, and FAK cleavage. Surprisingly, despite anandamide inhibited cell proliferation, it increased c-MYC expression. Moreover anandamide inhibited AKT activation, whilst it induced a sustained activation of ERK, JNK, and p38. Finally, anandamide synergized with TNF-a in the cleavage of caspase-3. In conclusion, our findings suggest that anandamide, alone or in combination with TNF-a, may be a potential destructive agent in cartilage. Keywords: cannabinoids; chondrocyte physiology; apoptosis; signal transduction; TNF The endocannabinoid system is constituted by the cannabinoid receptors (CB 1 and CB 2 ), by the endocannabinoids (including anandamide [AEA] and others) and the machinery for their biosynthesis and metabolism.

show abstract

Section: Resultsmentioning

confidence: 80%

Endogenous cannabinoid anandamide impairs cell growth and induces apoptosis in chondrocytes

et al. 2014

View full text Add to dashboard Cite

show abstract

“…This possibility is supported by the fact that most insulin sensitizing medicines are able to inhibit ATP production in mitochondria (Fig. 1) [122]. This conclusion provides a unifying mechanism for insulin resistance in obesity and aging.…”

Section: Discussionmentioning

confidence: 86%

Mechanisms of insulin resistance in obesity

2013

Front. Med.

Self Cite

591

397

View full text Add to dashboard Cite

Obesity increases the risk for type 2 diabetes through induction of insulin resistance. Treatment of type 2 diabetes has been limited by little translational knowledge of insulin resistance although there have been several well-documented hypotheses for insulin resistance. In those hypotheses, inflammation, mitochondrial dysfunction, hyperinsulinemia and lipotoxicity have been the major concepts and have received a lot of attention. Oxidative stress, endoplasmic reticulum (ER) stress, genetic background, aging, fatty liver, hypoxia and lipodystrophy are active subjects in the study of these concepts. However, none of those concepts or views has led to an effective therapy for type 2 diabetes. The reason is that there has been no consensus for a unifying mechanism of insulin resistance. In this review article, literature is critically analyzed and reinterpreted for a new energy-based concept of insulin resistance, in which insulin resistance is a result of energy surplus in cells. The energy surplus signal is mediated by ATP and sensed by adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Decreasing ATP level by suppression of production or stimulation of utilization is a promising approach in the treatment of insulin resistance. In support, many of existing insulin sensitizing medicines inhibit ATP production in mitochondria. The effective therapies such as weight loss, exercise, and caloric restriction all reduce ATP in insulin sensitive cells. This new concept provides a unifying cellular and molecular mechanism of insulin resistance in obesity, which may apply to insulin resistance in aging and lipodystrophy.

show abstract

“…131 On the other hand, increased ATP level and inhibited AMPK activity have been implicated in the energy surplus state and most of the existing insulinsensitizing medications inhibit ATP production in the mitochondria. 122,132 Effective management strategies, for instance, weight loss and exercise can improve insulin resistance. 133,134 Additionally, neural mechanisms for glycemic control exist, although they are compromised in type 1 diabetes mellitus (T1DM) and the late stage of T2DM which is termed as hypoglycemia associated autonomic failure (HAAF).…”

Section: Insulin Resistance and T2dmmentioning

confidence: 99%

<p>Converging Relationships of Obesity and Hyperuricemia with Special Reference to Metabolic Disorders and Plausible Therapeutic Implications</p>

Gong¹,

Su²,

Nguyen³

et al. 2020

DMSO

View full text Add to dashboard Cite

Background: Obesity and hyperuricemia mutually influence metabolic syndrome. This study discusses the metabolic relationships between obesity and hyperuricemia in terms of pathophysiology, complications, and treatments. Methods: We searched for preclinical or clinical studies on the pathophysiology, complications, and therapy of obesity and hyperuricemia on the PubMed database. Results: In this systemic review, we summarized our searching results on topics of pathophysiology, complications and therapeutic strategy. In pathophysiology, we firstly introduce genetic variations for obesity, hyperuricemia and their relationships by genetic studies. Secondly, we talk about the epigenetic influences on obesity and hyperuricemia. Thirdly, we describe the central metabolic regulation and the role of hyperuricemia. Then, we refer to the character of adipose tissue inflammation and oxidative stress in the obesity and hyperuricemia. In the last part of this topic, we reviewed the critical links of gut microbiota in the obesity and hyperuricemia. In the following part, we review the pathophysiology of major complications in obesity and hyperuricemia including insulin resistance and type 2 diabetes mellitus, chronic kidney disease, cardiovascular diseases, and cancers. Finally, we recapitulate the therapeutic strategies especially the novel pharmaceutic interventions for obesity and hyperuricemia, which concurrently show the mutual metabolic influences between two diseases. Conclusion: The data reviewed here delineate the metabolic relationships between obesity and hyperuricemia, and provide a comprehensive overview of the therapeutic targets for the management of metabolic syndromes.

show abstract

Mitochondrial inhibitor as a new class of insulin sensitizer

Cited by 45 publications

References 83 publications

Endogenous cannabinoid anandamide impairs cell growth and induces apoptosis in chondrocytes

Endogenous cannabinoid anandamide impairs cell growth and induces apoptosis in chondrocytes

Mechanisms of insulin resistance in obesity

<p>Converging Relationships of Obesity and Hyperuricemia with Special Reference to Metabolic Disorders and Plausible Therapeutic Implications</p>

Contact Info

Product

Resources

About