Polydatin alleviates traumatic spinal cord injury by reducing microglial inflammation via regulation of iNOS and NLRP3 inflammasome pathway

Lv, Runxiao; Du, Lili; Liu, Xueyong; Zhou, Fenghua; Zhang, Zhiqiang; Zhang, Lixin

doi:10.1016/j.intimp.2019.02.006

Cited by 41 publications

(32 citation statements)

References 44 publications

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“…Although the induction of the NLRP3 inflammasome contributes to host defenses against infections, dysregulated inflammasomes are associated with many human diseases, such as cancer, autoimmune diseases, and inflammatory disorders [[29], [30], [31], [32],66]. Our findings that G6PD inhibition can attenuate inflammasome activation suggest a new approach for therapeutic intervention of inflammasome-associated diseases [67,68] with inflammasome as a target. Hence, a G6PD inhibitor such as Polydatin, might be considered as a therapeutic agent to attenuate inflammasome-associated diseases [67,68].…”

Section: Discussionmentioning

confidence: 77%

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Impaired inflammasome activation and bacterial clearance in G6PD deficiency due to defective NOX/p38 MAPK/AP-1 redox signaling

Yen

et al. 2020

Redox Biology

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Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the pentose phosphate pathway that modulates cellular redox homeostasis via the regeneration of NADPH. G6PD-deficient cells have a reduced ability to induce the innate immune response, thus increasing host susceptibility to pathogen infections. An important part of the immune response is the activation of the inflammasome. G6PD-deficient peripheral blood mononuclear cells (PBMCs) from patients and human monocytic (THP-1) cells were used as models to investigate whether G6PD modulates inflammasome activation. A decreased expression of IL-1β was observed in both G6PD-deficient PBMCs and PMA-primed G6PD-knockdown (G6PD-kd) THP-1 cells upon lipopolysaccharide (LPS)/adenosine triphosphate (ATP) or LPS/nigericin stimulation. The pro-IL-1β expression of THP-1 cells was decreased by G6PD knockdown at the transcriptional and translational levels in an investigation of the expression of the inflammasome subunits. The phosphorylation of p38 MAPK and downstream c-Fos expression were decreased upon G6PD knockdown, accompanied by decreased AP-1 translocation into the nucleus. Impaired inflammasome activation in G6PD-kd THP-1 cells was mediated by a decrease in the production of reactive oxygen species (ROS) by NOX signaling, while treatment with hydrogen peroxide (H 2 O 2 ) enhanced inflammasome activation in G6PD-kd THP-1 cells. G6PD knockdown decreased Staphylococcus aureus and Escherichia coli clearance in G6PD-kd THP-1 cells and G6PD-deficient PBMCs following inflammasome activation. These findings support the notion that enhanced pathogen susceptibility in G6PD deficiency is, in part, due to an altered redox signaling, which adversely affects inflammasome activation and the bactericidal response.Abbreviations: G6PD, glucose-6-phosphate dehydrogenase; NADPH, reduced form of nicotinamide adenine dinucleotide phosphate; NOX, NADPH oxidase; NO, nitric oxide; NOS, nitric oxide synthase; UP-LPS, ultrapure lipopolysaccharide; PMA, phorbol 12-myristate 13-acetate; ATP, adenosine triphosphate; MAPK, mitogenactivated protein kinases; AP-1, activator protein 1; ROS, reactive oxygen species; PBMC, peripheral blood mononuclear cells; H 2 O 2 , hydrogen peroxide; THP-1, human monocytic cells; G6PD-kd, G6PD knockdown

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Section: Discussionmentioning

confidence: 77%

“…Our findings that G6PD inhibition can attenuate inflammasome activation suggest a new approach for therapeutic intervention of inflammasome-associated diseases [67,68] with inflammasome as a target. Hence, a G6PD inhibitor such as Polydatin, might be considered as a therapeutic agent to attenuate inflammasome-associated diseases [67,68].…”

Section: Discussionmentioning

confidence: 99%

Impaired inflammasome activation and bacterial clearance in G6PD deficiency due to defective NOX/p38 MAPK/AP-1 redox signaling

Yen

et al. 2020

Redox Biology

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“…SCI consists of a two-step process including a primary immediate mechanical injury followed by an inflammatory process and apoptosis, which is characterized by activation of glial cells and infiltration of leukocytes that exacerbates tissue damage by releasing reactive oxygen species, pro-inflammatory cytokines/chemokines, proteases, and lysosome enzymes [37, 38]. In addition to the major pro-inflammatory transcription factor NF-κB-mediated neuroinflammatory responses, nitric oxide (NO), also play key roles in pathophysiology of SCI [39–41]. Based on our results, PGRN can act as a protective target by regulating the inflammatory response after SCI.…”

Section: Discussionmentioning

confidence: 99%

Progranulin deficiency exacerbates spinal cord injury by promoting neuroinflammation and cell apoptosis in mice

Wang

Zhang

Ndong

et al. 2019

J Neuroinflammation

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PurposeSpinal cord injury (SCI) often results in significant and catastrophic dysfunction and disability and imposes a huge economic burden on society. This study aimed to determine whether progranulin (PGRN) plays a role in the progressive damage following SCI and evaluate the potential for development of a PGRN derivative as a new therapeutic target in SCI.MethodsPGRN-deficient (Gr−/−) and wild-type (WT) littermate mice were subjected to SCI using a weight-drop technique. Local PGRN expression following injury was evaluated by Western blotting and immunofluorescence. Basso Mouse Scale (BMS), inclined grid walking test, and inclined plane test were conducted at indicated time points to assess neurological recovery. Inflammation and apoptosis were examined by histology (Hematoxylin and Eosin (H&E) staining and Nissl staining, TUNEL assays, and immunofluorescence), Western blotting (from whole tissue protein for iNOS/p-p65/Bax/Bcl-2), and ex vivo ELISA (for TNFα/IL-1β/IL-6/IL-10). To identify the prophylactic and therapeutic potential of targeting PGRN, a PGRN derived small protein, Atsttrin, was conjugated to PLGA-PEG-PLGA thermosensitive hydrogel and injected into intrathecal space prior to SCI. BMS was recorded for neurological recovery and Western blotting was applied to detect the inflammatory and apoptotic proteins.ResultsAfter SCI, PGRN was highly expressed in activated macrophage/microglia and peaked at day 7 post-injury. Grn−/− mice showed a delayed neurological recovery after SCI at day 21, 28, 35, and 42 post-injury relative to WT controls. Histology, TUNEL assay, immunofluorescence, Western blotting, and ELISA all indicated that Grn−/− mice manifested uncontrolled and expanded inflammation and apoptosis. Administration of control-released Atsttrin could improve the neurological recovery and the pro-inflammatory/pro-apoptotic effect of PGRN deficiency.ConclusionPGRN deficiency exacerbates SCI by promoting neuroinflammation and cellular apoptosis, which can be alleviated by Atsttrin. Collectively, our data provide novel evidence of using PGRN derivatives as a promising therapeutic approach to improve the functional recovery for patients with spinal cord injury.

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“…[ 87 , 88 ]. It has been demonstrated that polydatin could attenuate traumatic spinal cord injury by inhibiting microglial inflammation via modulation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and inducible nitric oxide synthase pathways [ 89 ].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Protective Effects of Polydatin Against Dementia-Related Disorders

Tang

2020

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: Dementia is a collection of symptoms affecting a person’s cognition. Dementia is debilitating, and therefore, finding an effective treatment is of the utmost importance. Resveratrol, which exhibits neuroprotective effects, has low bioavailability. However, it’s glucoside polydatin is more bioavailable. Here, the evidence that supports the protective role of polydatin against dementia-related diseases such as Alzheimer’s disease, vascular dementia, alcohol-related dementia, and Lewy body dementias is presented. The beneficial effects of polydatin from a mechanistic perspective are specifically emphasized in this review. Future directions in this area of research are also discussed.

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Polydatin alleviates traumatic spinal cord injury by reducing microglial inflammation via regulation of iNOS and NLRP3 inflammasome pathway

Cited by 41 publications

References 44 publications

Impaired inflammasome activation and bacterial clearance in G6PD deficiency due to defective NOX/p38 MAPK/AP-1 redox signaling

Impaired inflammasome activation and bacterial clearance in G6PD deficiency due to defective NOX/p38 MAPK/AP-1 redox signaling

Progranulin deficiency exacerbates spinal cord injury by promoting neuroinflammation and cell apoptosis in mice

Protective Effects of Polydatin Against Dementia-Related Disorders

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