Regenerating islet‐derived protein 3 gamma (Reg3g) ameliorates tacrolimus‐induced pancreatic β‐cell dysfunction in mice by restoring mitochondrial function

Li, Senlin; Zhou, Hong; Xie, Mengyuan; Zhang, Zijun; Gou, Jing; Yang, Jian; Tian, Cheng; Ma, Kun; Wang, Cong Yi; Liu, Yi; Li, Qing; Peng, Wen; Xiang, Ming

doi:10.1111/bph.15803

Cited by 12 publications

(4 citation statements)

References 60 publications

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“…One study showed that exogenous delivery of REG3G contributes to the progression of chronic pancreatitis towards neoplasia [98]. At the same time, another study showed that it ameliorates pancreatic β-cell dysfunction in mice [99]. Previous publications demonstrated that Cre recombinase activity is increased in female mice compared to male mice [37,100] and that tamoxifen treatment may have a different effect on female and male mice [101][102][103][104].…”

Section: Discussionmentioning

confidence: 99%

Krüppel-like Factor 5 Plays an Important Role in the Pathogenesis of Chronic Pancreatitis

Alavi,

Mejia-Bautista,

Tang

et al. 2023

Cancers

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Chronic pancreatitis results in the formation of pancreatic intraepithelial neoplasia (PanIN) and poses a risk of developing pancreatic cancer. Our previous study demonstrated that Krüppel-like factor 5 (KLF5) is necessary for forming acinar-to-ductal metaplasia (ADM) in acute pancreatitis. Here, we investigated the role of KLF5 in response to chronic injury in the pancreas. Human tissues originating from chronic pancreatitis patients showed increased levels of epithelial KLF5. An inducible genetic model combining the deletion of Klf5 and the activation of KrasG12D mutant expression in pancreatic acinar cells together with chemically induced chronic pancreatitis was used. The chronic injury resulted in increased levels of KLF5 in both control and KrasG12D mutant mice. Furthermore, it led to numerous ADM and PanIN lesions and extensive fibrosis in the KRAS mutant mice. In contrast, pancreata with Klf5 loss (with or without KrasG12D) failed to develop ADM, PanIN, or significant fibrosis. Furthermore, the deletion of Klf5 reduced the expression level of cytokines and fibrotic components such as Il1b, Il6, Tnf, Tgfb1, Timp1, and Mmp9. Notably, using ChIP-PCR, we showed that KLF5 binds directly to the promoters of Il1b, Il6, and Tgfb1 genes. In summary, the inactivation of Klf5 inhibits ADM and PanIN formation and the development of pancreatic fibrosis.

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Section: Discussionmentioning

confidence: 99%

Krüppel-like Factor 5 Plays an Important Role in the Pathogenesis of Chronic Pancreatitis

Alavi,

Mejia-Bautista,

Tang

et al. 2023

Cancers

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“…AMPK, as a heterotrimeric Ser/Thr kinase, is stimulated by variations in the cellular ratio of AMP to ATP, which acts as an energy sensor to regulate oxidative stress and energy homeostasis, promoting mitochondrial functionality and repressing degenerative nerve diseases [ 17 , 18 ]. The anti-inflammatory effect of AMPK activation has been revealed, which was achieved by lowering the levels of neuron-mediated inflammatory cytokines [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

Perisciatic Nerve Dexmedetomidine Alleviates Spinal Oxidative Stress and Improves Peripheral Mitochondrial Dynamic Equilibrium in a Neuropathic Pain Mouse Model in an AMPK-Dependent Manner

Mei

Chen

et al. 2022

Disease Markers

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Neuropathic pain (NPP) is a debilitating clinical condition that presently has few effective treatments. NPP is caused by uncontrolled central oxidative stress and inflammation. Preliminary studies indicate that dexmedetomidine (DEX), an agonist of the alpha-2 adrenergic receptor, is beneficial for treating NPP. In this paper, the effects of administering DEX around injured nerves in a chronic constriction injury- (CCI-) induced neuropathic pain mouse model are investigated. According to the results, the perineural DEX significantly reversed the decline in the mechanical threshold and thermal latency in CCI mice ( p < 0.001 ). In the peripherally affected ischiadic nerve, the perineuronal DEX upregulated the expressions of pAMPK, OPA1, and SNPH but not Drp1 or KIF5B. The aforementioned effects of administering DEX can be partially reversed by compound C, a selective and reversible inhibitor of AMP-activated protein kinase (AMPK). Furthermore, it was found that perineural DEX significantly inhibited the CCI-induced upregulation of the immediate early gene c-Fos, overexpression of the inflammatory factors tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), attenuation of the NADH dehydrogenase complexes I, II, III, and IV, and the repression of ATP, SOD, and GSH in the dorsal horn of the spinal cord (DHSC) ( p < 0.01 ). These findings indicate that perineuronal DEX protected the injured ischiadic nerves and attenuated neuropathic pain via AMPK activation to improve energy supply in the peripheral injured nerves, alleviate the inflammatory factor release, and inhibit oxidative stress in the DHSC.

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“…The culture system in the Transwell was consistent with that on the well plates. Additionally, tacrolimus (HY-13756, MedChemExpress, Monmouth Junction, NJ, USA) was dissolved in dimethyl sulfoxide (DMSO, Sigma-Aldrich, Merck, Darmstadt, Germany), and its concentration was adjusted to 800 ng/mL in DMEM complete medium [ 28 ]. Stattic, a potent STAT3 inhibitor, (HY-13818, MedChemExpress), was also dissolved in DMSO, and its concentration was adjusted to 100 μm in the DMEM complete medium.…”

Section: Methodsmentioning

confidence: 99%

Human Menstrual Blood-Derived Stem Cells Protect against Tacrolimus-Induced Islet Dysfunction via Cystathionine β-Synthase Mediated IL-6/STAT3 Inactivation

Fu,

Zhang,

Zhang

et al. 2024

Biomolecules

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Diabetes imposes a huge burden worldwide. Islet transplantation is an alternative therapy for diabetes. However, tacrolimus, a kind of immunosuppressant after organ transplantation, is closely related to post-transplant diabetes mellitus. Mesenchymal stem cells (MSCs) have attracted interest for their potential to alleviate diabetes. In vivo experiments revealed that human menstrual blood-derived stem cells (MenSCs) treatment improved tacrolimus-induced blood glucose, body weight, and glucose tolerance disorders in mice. RNA sequencing was used to analyze the potential therapeutic targets of MenSCs. In this study, we illustrated that cystathionine β-synthase (CBS) contributed to tacrolimus -induced islet dysfunction. Using β-cell lines (MIN6, β-TC-6), we demonstrated that MenSCs ameliorated tacrolimus-induced islet dysfunction in vitro. Moreover, MenSC reduced the tacrolimus-induced elevation of CBS levels and significantly enhanced the viability, anti-apoptotic ability, glucose-stimulated insulin secretion (GSIS), and glycolytic flux of β-cells. We further revealed that MenSCs exerted their therapeutic effects by inhibiting CBS expression to activate the IL6/JAK2/STAT3 pathway. In conclusion, we showed that MenSCs may be a potential strategy to improve tacrolimus-induced islet dysfunction.

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Regenerating islet‐derived protein 3 gamma (Reg3g) ameliorates tacrolimus‐induced pancreatic β‐cell dysfunction in mice by restoring mitochondrial function

Cited by 12 publications

References 60 publications

Krüppel-like Factor 5 Plays an Important Role in the Pathogenesis of Chronic Pancreatitis

Krüppel-like Factor 5 Plays an Important Role in the Pathogenesis of Chronic Pancreatitis

Perisciatic Nerve Dexmedetomidine Alleviates Spinal Oxidative Stress and Improves Peripheral Mitochondrial Dynamic Equilibrium in a Neuropathic Pain Mouse Model in an AMPK-Dependent Manner

Human Menstrual Blood-Derived Stem Cells Protect against Tacrolimus-Induced Islet Dysfunction via Cystathionine β-Synthase Mediated IL-6/STAT3 Inactivation

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