Selective inhibition of PKR by C16 accelerates diabetic wound healing by inhibiting NALP3 expression in mice

Karnam, Kalyani; Sedmaki, Kavitha; Sharma, Pravesh; Venuganti, Venkata Vamsi Krishna; Kulkarni, Onkar P.

doi:10.1007/s00011-022-01667-y

Cited by 4 publications

(5 citation statements)

References 37 publications

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“…Based on the analysis of the enrichment results, it can be concluded that knockdown of the EIF2AK2 gene reduces the proliferation and migration of PANC-1 cells, and can promote their apoptosis and inhibit the cell cycle. The experimental results that knockdown of EIF2AK2 promotes apoptosis in PANC-1 cells are clearly inconsistent with the findings reported above in the literature ( 36 ). Therefore it is necessary to review the basic principles of the EIF2AK2 pathway.…”

Section: Discussioncontrasting

confidence: 98%

“…In addition, EIF2AK2 was considered to be a tumor suppressor based on its proapoptotic activity. The first experimental evidence of EIF2AK2 tumor-suppressing activity was provided by a catalytically inactivated EIF2AK2 mutant that inhibited endogenous EIF2AK2 activity in a dominantly negative manner (36). Its low expression level is considered to be associated with cancer phenotypes, such as active cell proliferation, poor pathological differentiation or poor patient prognosis, including in head and neck squamous cell carcinoma, breast cancer, hepatocellular carcinoma, colon cancer, bile duct cancer and primary lung cancer (37)(38)(39)(40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

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Eukaryotic translation initiation factor 2α kinase 2 in pancreatic cancer: An approach towards managing clinical prognosis and molecular immunological characterization

Du,

Wang,

et al. 2023

Oncol Lett

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Most patients with pancreatic cancer are already in the late stages of the disease when they are diagnosed, and pancreatic cancer is a deadly disease with a poor prognosis. With the advancement of research, immunotherapy has become a new focus in the treatment of tumors. To the best of our knowledge, there is currently no reliable diagnostic or prognostic marker for pancreatic cancer; therefore, the present study investigated the potential of eukaryotic translation initiation factor 2α kinase 2 (EIF2AK2) as a predictive and diagnostic marker for pancreatic cancer. Immunohistochemical staining of clinical samples independently verified that EIF2AK2 expression was significantly higher in clinically operated pancreatic cancer tissues than in adjacent pancreatic tissues., and EIF2AK2 expression and differentially expressed genes (DEGs) were identified using downloadable RNA sequencing data from The Cancer Genome Atlas and Genomic Tumor Expression Atlas. In addition, Gene Ontology/Kyoto Encyclopedia of Genes and Genomes analyses and immune cell infiltration were used for functional enrichment analysis of EIF2AK2-associated DEGs. The clinical importance of EIF2AK2 was also determined using Kaplan-Meier survival, Cox regression and time-dependent survival receiver operating characteristic curve analyses, and a predictive nomogram model was generated. Finally, the functional role of EIF2AK2 was assessed in PANC-1 cells using a short hairpin RNA-EIF2AK2 knockdown approach, including CCK-8, wound healing assay, cell cycle and apoptosis assays. The findings suggested that EIF2AK2 may have potential as a diagnostic and prognostic biomarker for patients with pancreatic cancer. Furthermore, EIF2AK2 may provide a new therapeutic target for patients with pancreatic cancer.

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Section: Discussioncontrasting

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Eukaryotic translation initiation factor 2α kinase 2 in pancreatic cancer: An approach towards managing clinical prognosis and molecular immunological characterization

Du,

Wang,

et al. 2023

Oncol Lett

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“…Maintaining the appropriate balance of TGF-β is important for controlling in ammation and enabling recovery [56]. In chronic in ammatory states, the production of IL-4 and TGF-β can increase the production of M2 macrophages to reduce in ammation and promote healing [57]. The study results show that moxibustion treatment, MC3482 intervention, and a combination of moxibustion and MC3482 can relieve in ammation by regulating in ammatory cytokines expression.…”

Section: Discussionmentioning

confidence: 99%

Moxibustion alleviates inflammation via SIRT5 post-translational modification and macrophage polarization

Zhang,

Gou

et al. 2023

Preprint

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Background Macrophage polarization plays an essential role in the anti-inflammation process. Moxibustion, a traditional Chinese medicine therapy, has been reported to have an anti-inflammatory effect via enhancing α-ketoglutarate (α-KG) and succinate levels. Succinate/α-KG ratio is a hallmark of M1 and M2 macrophage shift. Glutamate dehydrogenase 1 (GLUD1) is a vital enzyme for α-KG production and can be deacetylated by Sirtuin5 (SIRT5). Currently, the role of moxibustion in SIRT5-GLUD1-α-KG-related macrophage alteration in inflammatory diseases has not been discussed yet. Methods In this study, complete Freund's adjuvant (CFA)-induced adjuvant arthritis models were established. On day 4 post-CFA, moxibustion and acupoint MC3482 injection were administered. Foot volume was measured before and after the model was established, and after the moxibustion and acupoint injection interventions. ELISA assays were then performed to quantify inflammatory factors, including IL-1β, TNF-α, IL-4, TGF-β, succinate, and α-ketoglutarate (α-KG). Flow cytometry (FCM) and immunofluorescence were used to test M1- and M2-like macrophage expressions in the right arthrodial cartilages of mice. Furthermore, western blotting and immunoprecipitation (IP) were used to detect SIRT5, GLUD1, and GLUD1 succinylation expressions. Results Moxibustion and SIRT5 desuccinylation inhibitor MC3482 decreased inflammation by increasing M2 macrophage and reducing M1 macrophage levels in CFA model. The potential mechanism may relate to the effects of moxibustion and SIRT5 inhibition, which could invert succinate and α-KG levels in the CFA group, which displayed low succinate, high α-KG and increased GLUD1 succinylation modification after treatment. Conclusion This study supports that moxibustion's anti-inflammation effects are related to the consequences of macrophage conversion after SIRT5 post-translational modification.

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“… 156 Kulkarni and colleagues evaluated the therapeutic potential of PKR inhibitors in delayed wound healing of diabetic patients using C16 hydrogel. 83 Selective PKR inhibition with C16 fostered faster wound healing, decreased levels of p-PKR and p-eIF2α, enhanced angiogenesis, alleviated inflammatory cell accumulation and improved wound strength. 83 Therefore, C16 can deliver a new therapeutic effect for treating DWH via the regulation of pyroptosis.…”

Section: Suppressing Pyroptosis-dependent Signaling In Therapeutic Re...mentioning

confidence: 99%

“… 11 Diabetic wounds and macrophages treated with LPS and high glucose showed elevated levels of NALP3 and PKR. 83 Caspase-1 and NALP3 gene-knockout mice exhibited diminished inflammatory response during the early stages of injury, resulting in impaired healing. 84 PKR was activated by the Caspase-1 and NALP3 inflammasome signaling axis in mice with diabetes and delayed wound healing.…”

Section: Pyroptosis-dependent Signaling Pathways In the Progression O...mentioning

confidence: 99%

The Mechanism of Pyroptosis and Its Application Prospect in Diabetic Wound Healing

Al Mamun,

Shao,

Geng

et al. 2024

JIR

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Pyroptosis defines a form of pro-inflammatory-dependent programmed cell death triggered by gasdermin proteins, which creates cytoplasmic pores and promotes the activation and accumulation of immune cells by releasing several pro-inflammatory mediators and immunogenic substances upon cell rupture. Pyroptosis comprises canonical (mediated by Caspase-1) and non-canonical (mediated by Caspase-4/5/11) molecular signaling pathways. Numerous studies have explored the contributory roles of inflammasome and pyroptosis in the progression of multiple pathological conditions such as tumors, nerve injury, inflammatory diseases and metabolic disorders. Accumulating evidence indicates that the activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome results in the activation of pyroptosis and inflammation. Current evidence suggests that pyroptosis-dependent cell death plays a progressive role in the development of diabetic complications including diabetic wound healing (DWH) and diabetic foot ulcers (DFUs). This review presents a brief overview of the molecular mechanisms underlying pyroptosis and addresses the current research on pyroptosis-dependent signaling pathways in the context of DWH. In this review, we also present some prospective therapeutic compounds/agents that can target pyroptotic signaling pathways, which may serve as new strategies for the effective treatment and management of diabetic wounds.

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Selective inhibition of PKR by C16 accelerates diabetic wound healing by inhibiting NALP3 expression in mice

Cited by 4 publications

References 37 publications

Eukaryotic translation initiation factor 2α kinase 2 in pancreatic cancer: An approach towards managing clinical prognosis and molecular immunological characterization

Eukaryotic translation initiation factor 2α kinase 2 in pancreatic cancer: An approach towards managing clinical prognosis and molecular immunological characterization

Moxibustion alleviates inflammation via SIRT5 post-translational modification and macrophage polarization

The Mechanism of Pyroptosis and Its Application Prospect in Diabetic Wound Healing

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