JNK signaling pathway in metabolic disorders: An emerging therapeutic target

Garg, Richa; Kumariya, Sanjana; Katekar, Roshan; Verma, Sudhir Kumar; Goand, Umesh K.; Gayen, Jiaur R.

doi:10.1016/j.ejphar.2021.174079

Cited by 23 publications

(29 citation statements)

References 163 publications

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“…We first proved that miR-1a-3p modulated sFRP1/Wnt/PCP-JNK signaling. This signaling axis has been linked to oxidative stress, metabolic dysfunction, and inflammatory responses, which is consistent with our research [ 40 ].…”

Section: Discussionsupporting

confidence: 92%

Highly Purified Eicosapentaenoic Acid Alleviates the Inflammatory Response and Oxidative Stress in Macrophages during Atherosclerosis via the miR-1a-3p/sFRP1/Wnt/PCP-JNK Pathway

Zang

Chen

Shen

et al. 2022

Oxidative Medicine and Cellular Longevity

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Highly purified eicosapentaenoic acid (EPA) has shown great effects in the prevention of atherosclerosis. In a murine model, it significantly reduced plaque accumulation, lowered plasma lipid levels, and decreased inflammation levels, which was also observed in vitro. Using microRNA sequencing, we identified differentially expressed microRNAs, among which miR-1a-3p was selected for further validation. Overexpression of miR-1a-3p in RAW264.7 cells worsened lipid accumulation, increased oxidative stress, and exacerbated inflammatory responses whereas its downregulation produced the opposite results. Potential targets of miR-1a-3p were analyzed by prediction tools. Then, secreted frizzled-related protein 1 (sFRP1), an antagonist of the Wnt pathway, was confirmed as the target gene of miR-1a-3p by a dual-luciferase reporter assay. Further research showed that in macrophages, EPA influenced the activation of the Wnt/planar cell polarity-c-Jun N-terminal kinase (Wnt/PCP-JNK) axis, which is consistent with the phenomenon that miR-1a-3p has an impact on this same axis. Collectively, our findings suggest that EPA mitigates inflammatory responses and oxidative responses both in vivo and in vitro by targeting the miR-1a-3p/sFRP1/Wnt/PCP-JNK axis in macrophages, which may explain the cardioprotective role of EPA and promote the application of EPA in clinical practice.

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Section: Discussionsupporting

confidence: 92%

Highly Purified Eicosapentaenoic Acid Alleviates the Inflammatory Response and Oxidative Stress in Macrophages during Atherosclerosis via the miR-1a-3p/sFRP1/Wnt/PCP-JNK Pathway

Zang

Chen

Shen

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…IKK-NFĸB pathways have also been implicated in EMP by ourselves and others (Alameda et al, 2011; Alameda et al, 2016; Goktuna et al, 2018; Sailem and Bakal, 2017; Sero et al, 2015). Increases in JNK activity during EMP in particular are likely for downregulation of Insulin signalling, and upregulation of AMPK signalling a number of different means, in particular via inhibitory IRS1/2 phosphorylation by JNK kinases (Copps and White, 2012; Garg et al, 2021; Holzer et al, 2011; Solinas et al, 2006; Solinas et al, 2007) (Figure 9B).…”

Section: Discussionmentioning

confidence: 99%

Epithelial-Mesenchymal Plasticity is regulated by inflammatory signalling networks coupled to cell morphology

Arias-Garcia

Rickman

Sero

et al. 2019

Preprint

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The shape, size, and architecture of the nucleus determines the output of transcriptional programmes. As such, the ability of the nucleus to resist deformation and maintain its shape is essential for homeostasis. Conversely, changes in nuclear shape can alter transcription and cell state. The ability of cells to deform their nuclei is also essential for cells to invade confined spaces. But how cells set the extent of nuclear deformability in response to their environment is unclear. Here we show that the cell-cell adhesion protein JAM3 regulates nuclear shape. In epithelial cells, JAM3 is required for maintenance of nuclear shape by organizing microtubule polymers and promoting LMNA stabilization in the nuclear membrane. Depletion of JAM3 in normal epithelial cells leads to dysmorphic nuclei, which leads to differentiation into a mesenchymal-like state. Inhibiting the actions of kinesins in JAM3 depleted cells restores nuclear morphology and prevents differentiation into the mesenchymal-like state. Critically, JAM3 expression is predictive of disease progression. Thus JAM3 is a molecule which allows cells to control cell fates in response to the presence of neighbouring cells by tuning the extent of nuclear deformability. 3 IntroductionNuclear shape, size and architecture define the biophysics of key cellular processes such as transcription, replication, mRNA export, and DNA damage repair 1-4 . But nuclei are malleable viscoelastic structures 5, 6 that are frequently being stretched, strained, and compressed both by extracellular forces 7 , and the internal cytoskeleton 8-12 . Mechanisms have evolved to maintain nuclear shape and genome organization when cells are exposed to these forces 13 .Indeed, dysregulation of nuclear shape is coincident with numerous diseases including: muscular dystrophies, heart disease, and aging disorders such as progeria [14][15][16][17][18] . Thus in many cells, maintaining nuclear shape is essential for homeostasis.But while clearly maintenance of nuclear shape, size, and genome organization is essential for cellular homeostasis, transcriptional programmes that alter cell fate can be engaged by altering nuclear morphology and architecture 1,5,[19][20][21][22] . For example, nuclei undergo extensive shape changes that drive differentiation during development 23 . One means by which alteration in nuclear shape affects transcription is by affecting the nuclear translocation dynamics of transcription factors such as YAP/TAZ and NF-κB 24, 25 . Thus while in some cell types nuclear shape and genome organization are robust to deformation, in other cell types the nucleus is highly deformable.The importance of maintaining nuclear shape for cell, tissue, and organism homeostasis is highlighted by the fact that changes in nuclear morphology and genome organization are associated with cancer 4, 26 . For example, nuclear rupture is frequently an oncogenic event 27,28 . Indeed, pathologists have used nuclear shape as a diagnostic for over a century 29 . Irregular nuclear shapes and sizes are hall...

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“…Obesity is usually characterized by the presence of high serum leptin levels in pro-portion to adiposity. In a situation of hyperleptinemia, increased cytokines can activate c-jun N-terminal kinase (JNK) and vice versa, both implicated in the generation of insulin resistance [ 10 ]. Leptin triggers signal transducers as well as the activator of transcription 3 (STAT3) and p38 mitogen-activated protein kinase (p38MAPK) phosphorylation, thus aggravating the inflammatory environment by enhancing synthesis of pro-inflammatory cytokines [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Changes in Lipid Metabolism Enzymes in Rat Epididymal Fat after Chronic Central Leptin Infusion Are Related to Alterations in Inflammation and Insulin Signaling

Casado

Canelles

Arilla‐Ferreiro

et al. 2023

IJMS

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Leptin inhibits food intake and reduces the size of body fat depots, changing adipocyte sensitivity to insulin to restrain lipid accrual. This adipokine may modulate the production of cytokines that could diminish insulin sensitivity, particularly in visceral adipose tissue. To explore this possibility, we examined the effects of chronic central administration of leptin on the expression of key markers of lipid metabolism and its possible relationship with changes in inflammatory- and insulin-signaling pathways in epididymal adipose tissue. Circulating non-esterified fatty acids and pro- and anti-inflammatory cytokines were also measured. Fifteen male rats were divided into control (C), leptin (L, icv, 12 μg/day for 14 days), and pair-fed (PF) groups. We found a decrease in the activity of glucose-6-phosphate dehydrogenase and malic enzyme in the L group, with no changes in the expression of lipogenic enzymes. A reduction in the expression of lipoprotein lipase and carnitine palmitoyl-transferase-1A, together with a decrease in the phosphorylation of insulin-signaling targets and a low-grade inflammatory pattern, were detected in the epididymal fat of L rats. In conclusion, the decrease in insulin sensitivity and increased pro-inflammatory environment could regulate lipid metabolism, reducing epididymal fat stores in response to central leptin infusion.

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JNK signaling pathway in metabolic disorders: An emerging therapeutic target

Cited by 23 publications

References 163 publications

Highly Purified Eicosapentaenoic Acid Alleviates the Inflammatory Response and Oxidative Stress in Macrophages during Atherosclerosis via the miR-1a-3p/sFRP1/Wnt/PCP-JNK Pathway

Highly Purified Eicosapentaenoic Acid Alleviates the Inflammatory Response and Oxidative Stress in Macrophages during Atherosclerosis via the miR-1a-3p/sFRP1/Wnt/PCP-JNK Pathway

Epithelial-Mesenchymal Plasticity is regulated by inflammatory signalling networks coupled to cell morphology

Changes in Lipid Metabolism Enzymes in Rat Epididymal Fat after Chronic Central Leptin Infusion Are Related to Alterations in Inflammation and Insulin Signaling

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