Molybdenum induces pancreatic β-cell dysfunction and apoptosis via interdependent of JNK and AMPK activation-regulated mitochondria-dependent and ER stress-triggered pathways

Yang, Tsung‐Yuan; Yen, Chi-Hua; Lee, Kuan-I; Su, Chin-Chuan; Yang, Ching‐Yao; Wu, Chi‐Rei; Hsieh, Shang-Shu; Ueng, Kwo‐Chang; Huang, Chun-Fa

doi:10.1016/j.taap.2016.01.013

Cited by 27 publications

(23 citation statements)

References 57 publications

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“…ER stress has been reported to be involved in chemical-induced apoptosis in mammalian cells, including β-cells [ 20 ]. Thus, we next examined the effects of MBP on the expression of various ER stress markers in RIN-m5F cells.…”

Section: Resultsmentioning

confidence: 99%

“…JNK and AMPK-mediated signaling pathways play important roles in toxic chemical-induced apoptosis [ 20 , 21 ]. We next examined whether JNK/AMPK activation was involved in MBP- induced β-cell apoptosis.…”

Section: Resultsmentioning

confidence: 99%

“…ER stress is associated with numerous pathophysiological conditions in various human diseases, including DM [ 49 , 50 ]. Growing evidence has shown that toxic chemical-induced ER stress is involved in the process of apoptosis in β-cells, skeletal muscle-derived myoblasts, and pulmonary alveolar epithelial cells [ 17 , 20 , 21 , 51 , 52 , 53 ]. Recently, Liu et al [ 17 ] and Huang et al [ 37 ] indicated that MBP exposure significantly induced the AMPK/ERK/Akt signal-regulated ER stress-triggered apoptotic pathway, resulting in type 2 pulmonary alveolar epithelial cell and neuronal cell death; however, this effect has not been evaluated in β-cells.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of the JNK pathway induced by diverse stimuli (such as cytokines, Aβ peptides, oxidative stress, or toxic chemicals) has been identified as a critical factor in pathological cell death, associated with the development of many diseases, including DM [ 55 , 56 ]. Accumulating evidence suggests that a marked activation of the JNK signal in pancreatic β-cells exposed to toxic insults subsequently leads to β-cell dysfunction and apoptotic cell death [ 20 , 21 , 28 ], implying that JNK plays an important role in β-cell damage. Furthermore, AMPK is a multimeric serine/threonine protein kinase, composed of α- (catalytic), β- (scaffold), and γ- (regulatory) subunits [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

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4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene, a Major Active Metabolite of Bisphenol A, Triggers Pancreatic β-Cell Death via a JNK/AMPKα Activation-Regulated Endoplasmic Reticulum Stress-Mediated Apoptotic Pathway

Huang

Yang

et al. 2021

IJMS

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4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), a major active metabolite of bisphenol A (BPA), is generated in the mammalian liver. Some studies have suggested that MBP exerts greater toxicity than BPA. However, the mechanism underlying MBP-induced pancreatic β-cell cytotoxicity remains largely unclear. This study demonstrated the cytotoxicity of MBP in pancreatic β-cells and elucidated the cellular mechanism involved in MBP-induced β-cell death. Our results showed that MBP exposure significantly reduced cell viability, caused insulin secretion dysfunction, and induced apoptotic events including increased caspase-3 activity and the expression of active forms of caspase-3/-7/-9 and PARP protein. In addition, MBP triggered endoplasmic reticulum (ER) stress, as indicated by the upregulation of GRP 78, CHOP, and cleaved caspase-12 proteins. Pretreatment with 4-phenylbutyric acid (4-PBA; a pharmacological inhibitor of ER stress) markedly reversed MBP-induced ER stress and apoptosis-related signals. Furthermore, exposure to MBP significantly induced the protein phosphorylation of JNK and AMP-activated protein kinase (AMPK)α. Pretreatment of β-cells with pharmacological inhibitors for JNK (SP600125) and AMPK (compound C), respectively, effectively abrogated the MBP-induced apoptosis-related signals. Both JNK and AMPK inhibitors also suppressed the MBP-induced activation of JNK and AMPKα and of each other. In conclusion, these findings suggest that MBP exposure exerts cytotoxicity on β-cells via the interdependent activation of JNK and AMPKα, which regulates the downstream apoptotic signaling pathway.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene, a Major Active Metabolite of Bisphenol A, Triggers Pancreatic β-Cell Death via a JNK/AMPKα Activation-Regulated Endoplasmic Reticulum Stress-Mediated Apoptotic Pathway

Huang

Yang

et al. 2021

IJMS

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“…Liraglutide has been shown to increase β-cell viability, however this effect has been shown to be abated by several pathway blockers: the AMPK activator AICAR and the mTOR inhibitor rapamycin [6]. It has also been suggested that AMPK activation mediates the downstream mitochondrial-dependent and ER stress-triggered apoptotic pathways [15]. However, several previous studies have shown that AMPK regulates SREBP, thus reducing downstream lipogenesis and enhancing lipolysis.…”

Section: Discussionmentioning

confidence: 99%

Active subfractions of Abelmoschus esculentus substantially prevent free fatty acid-induced β cell apoptosis via inhibiting dipeptidyl peptidase-4

et al. 2017

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Lipotoxicity plays an important role in exacerbating type 2 diabetes mellitus (T2DM) and leads to apoptosis of β cells. Recently dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged as a useful tool in the treatment of T2DM. DPP-4 degrades type 1 glucagon-like peptide (GLP-1), and GLP-1 receptor (GLP-1R) signaling has been shown to protect β cells by modulating AMPK/mTOR, PI3K, and Bax. The anti-hyperglycemic effect of Abelmoschus esculentus (AE) is well known, however its mucilage makes it difficult to further examine this effect. In our recent report, a sequence of extraction steps was used to obtain a series of subfractions from AE, each with its own composition and property. Among them F1 (rich in quercetin glucosides and pentacyclic triterpene ester) and F2 (containing large amounts of carbohydrates and polysaccharides) were found to be especially effective in attenuating DPP-4 signaling, and to have the potential to counter diabetic nephropathy. Hence, the aim of the present study was to investigate whether AE subfractions can prevent the palmitate-induced apoptosis of β cells, and the putative signals involved. We demonstrated that AE, and especially 1 μg/mL of F2, decreased palmitate-induced apoptosis analyzed by flow cytometry. The result of western blot revealed that palmitate-induced decrease in GLP-1R and increase in DPP-4 were restored by F1 and F2. The DPP-4 inhibitor linagliptin decreased the expression of caspase 3, suggesting that DPP-4 is critically involved in apoptotic signaling. Analysis of enzyme activity revealed that palmitate increased the activity of DPP4 nearly 2 folds, while F2 especially inhibited the activation. In addition, AMPK/mTOR, PI3K and mitochondrial pathways were regulated by AE, and this attenuated the palmitate-induced signaling cascades. In conclusion, AE is useful to prevent the exacerbation of β cell apoptosis, and it could potentially be used as adjuvant or nutraceutical therapy for diabetes.

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Maduramicin ammonium impairs autophagic flux through activating AMPK‐mediated eIF2α‐ATF4 endoplasmic reticulum stress pathway in skeletal muscle

Chen,

Xie,

Liu

et al. 2024

J Sci Food Agric

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BACKGROUNDMaduramicin ammonium (MA), a widely used coccidiostat, has been reported to cause skeletal muscle degeneration in animals and even humans. In this study, we explore the underlying mechanism of its toxicity in skeletal muscle.RESULTSFirst, we observed that MA impaired autophagic flux which was evidenced by increased protein level of LC3‐II and p62 in skeletal myoblast C2C12 and L6 cell lines and rectus femoris muscle tissues of rats and broilers. Then, we found that MA induced eIF2α phosphorylation and ATF4 expression in the cells and tissues. Co‐treatment with ISRIB attenuated MA‐induced LC3‐II and p62 in C2C12 and L6 cells, suggesting that MA‐induced eIF2α‐ATF4 pathway contributed to impairment of autophagic flux in the cells. Lastly, we showed that MA activated AMPK signaling in skeletal muscle, since the phosphorylation of AMPK was increased by MA treatment in skeletal myoblast cell lines and muscle tissues. Furthermore, in AMPK downregulated C2C12 cells, MA‐induced LC3‐II, ATF4 and phosphorylation of eIF2α was reversed, supporting that AMPK was involved in the regulation of the eIF2α‐ATF4 pathway and autophagic flux during MA exposure.CONCLUSIONOur findings showed that MA impairs autophagic flux through activating the AMPK‐induced eIF2α‐ATF4 pathway in skeletal muscle. © 2024 Society of Chemical Industry.

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Molybdenum induces pancreatic β-cell dysfunction and apoptosis via interdependent of JNK and AMPK activation-regulated mitochondria-dependent and ER stress-triggered pathways

Cited by 27 publications

References 57 publications

4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene, a Major Active Metabolite of Bisphenol A, Triggers Pancreatic β-Cell Death via a JNK/AMPKα Activation-Regulated Endoplasmic Reticulum Stress-Mediated Apoptotic Pathway

4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene, a Major Active Metabolite of Bisphenol A, Triggers Pancreatic β-Cell Death via a JNK/AMPKα Activation-Regulated Endoplasmic Reticulum Stress-Mediated Apoptotic Pathway

Active subfractions of Abelmoschus esculentus substantially prevent free fatty acid-induced β cell apoptosis via inhibiting dipeptidyl peptidase-4

Maduramicin ammonium impairs autophagic flux through activating AMPK‐mediated eIF2α‐ATF4 endoplasmic reticulum stress pathway in skeletal muscle

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