Pigment epithelium‑derived factor facilitates NLRP3 inflammasome activation through downregulating cytidine monophosphate kinase 2: A potential treatment strategy for missed abortion

Zhang, Xi; Zhang, Kun; Zhang, Yi

doi:10.3892/ijmm.2020.4517

Cited by 9 publications

(9 citation statements)

References 34 publications

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“…LPS, a classic TLR4 agonist, has long been used to make preeclamptic models for years as LPS amplifies the TLR4/NF- κ B signaling to trigger trophoblastic inflammation [ 39 , 40 ]. Consistent with the latest research [ 37 , 52 ], our results showed that LPS significantly activated the TLR4/NF- κ B signaling, further contributing to the NLRP3 inflammasome-induced pyroptosis. Because of the release of the proinflammatory factors IL-1 β and IL-18, the NLRP3 inflammasome-induced pyroptosis is not only a crucial way to induce trophoblastic death in the preeclamptic placentas but also a possible amplifier of maternal systematic injury via triggering sterile inflammatory cascades.…”

Section: Discussionsupporting

confidence: 93%

Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome‐Induced Pyroptosis via Inhibiting the TLR4/NF‐κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia

Zhang

Liu

Zhong

et al. 2021

Oxidative Medicine and Cellular Longevity

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NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome-mediated pyroptosis is a crucial event in the preeclamptic pathogenesis, tightly linked with the uteroplacental TLR4/NF-κB signaling. Trophoblastic glycometabolism reprogramming has now been noticed in the preeclampsia pathogenesis, plausibly modulated by the TLR4/NF-κB signaling as well. Intriguingly, cellular pyroptosis and metabolic phenotypes may be inextricably linked and interacted. Metformin (MET), a widely accepted NF-κB signaling inhibitor, may have therapeutic potential in preeclampsia while the underlying mechanisms remain unclear. Herein, we investigated the role of MET on trophoblastic pyroptosis and its relevant metabolism reprogramming. The safety of pharmacologic MET concentration to trophoblasts was verified at first, which had no adverse effects on trophoblastic viability. Pharmacological MET concentration suppressed NLRP3 inflammasome-induced pyroptosis partly through inhibiting the TLR4/NF-κB signaling in preeclamptic trophoblast models induced via low-dose lipopolysaccharide. Besides, MET corrected the glycometabolic reprogramming and oxidative stress partly via suppressing the TLR4/NF-κB signaling and blocking transcription factor NF-κB1 binding on the promoter PFKFB3, a potent glycolytic accelerator. Furthermore, PFKFB3 can also enhance the NF-κB signaling, reduce NLRP3 ubiquitination, and aggravate pyroptosis. However, MET suppressed pyroptosis partly via inhibiting PFKFB3 as well. These results provided that the TLR4/NF-κB/PFKFB3 pathway may be a novel link between metabolism reprogramming and NLRP3 inflammasome-induced pyroptosis in trophoblasts. Further, MET alleviates the NLRP3 inflammasome-induced pyroptosis, which partly relies on the regulation of TLR4/NF-κB/PFKFB3-dependent glycometabolism reprogramming and redox disorders. Hence, our results provide novel insights into the pathogenesis of preeclampsia and propose MET as a potential therapy.

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Section: Discussionsupporting

confidence: 93%

Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome‐Induced Pyroptosis via Inhibiting the TLR4/NF‐κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia

Zhang

Liu

Zhong

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Moreover, the retention of the embryo sac in the uterus can result in the organization of soft tissues and close adhesion with the uterine wall, increasing the difficulty of detaching both, which can often cause incomplete clearance and result in continuous vaginal bleeding or infection. Some patients even require multiple clearings, which carry a higher risk of complications and even secondary infertility [ 12 , 13 ]. In this study, the combination of different drugs was used to treat MA patients, and the results showed that the time to embryo expulsion, duration of surgery, intraoperative bleeding, duration of vaginal bleeding, and bleeding volume were lower in the research group than in the control group, while the rate of complete abortion and primary curettage were significantly higher than in the control group.…”

Section: Discussionmentioning

confidence: 99%

Clinical Efficacy and Safety Study of Mifepristone with Misoprostol Treatment in Patients with Missed Abortion

Zhao¹,

Zhang

Lou³

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Currently, medication abortion is widely used in clinical practice in China. The aim of this study was to investigate the effect of mifepristone with misoprostol treatment on the efficacy of patients with missed abortion (MA) and the safety of this drug regimen. 95 patients with MA treated in our hospital from February 2019 to April 2021 were collected as the subjects of this study, and the patients were divided into the control and the research groups according to different treatment modalities. Among them, 46 cases in the control group were treated by diethylstilbestrol combined with oxytocin and 49 cases in the research group were treated by mifepristone combined with misoprostol, and both groups underwent curettage after medication. The rates of complete abortion, time of embryo expulsion, time of operation, intraoperative bleeding, time of postoperative vaginal bleeding, amount of vaginal bleeding, rate of one-time curettage, the levels of serum estradiol (E2), progesterone (P), β-chorionic gonadotropin (β-hCG), and interleukin-18 (IL-18), and the incidence of adverse effects in the two groups were examined and compared. Alanine transaminase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and serum creatinine (Scr) were used as indicators to evaluate the safety of the drug. The results showed that the rates of complete abortion and one-time curettage were significantly higher in the study group than in the control group, while the time of embryo expulsion, operation time, intraoperative bleeding, postoperative vaginal bleeding time, and vaginal bleeding were significantly lower than in the control group. The serum E2, P, and β-hCG levels before curettage in both groups were significantly higher, and IL-18 levels were significantly lower than those at the time of admission, with E2, P, and β-hCG levels increasing more and IL-18 levels decreasing more in the research group. After drug treatment, no abnormal changes in liver and kidney functions were observed in both groups, and the incidence of adverse reactions was at a similar and lower level in both groups. This shows that mifepristone with misoprostol is a safer and more effective drug regimen for the treatment of MA, which can regulate the levels of serum sex hormones and inflammatory factors in the body, promote the shedding of placental tissue, and create conditions for improving the rate of curettage.

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“…The NLRP3 inflammasome plays a central role in many acute and chronic inflammatory and degenerative diseases ( 35 – 38 ), but the mechanisms that control its activation are poorly understood. Recent studies have confirmed that CMPK2 plays a key role in NLRP3 activation, IL-1β production, and subsequent chronic inflammatory disease ( 26 , 27 ). We examined CMPK2 expression and NLRP3 inflammasome activation following SCI.…”

Section: Discussionmentioning

confidence: 94%

Electroacupuncture Inhibits NLRP3 Activation by Regulating CMPK2 After Spinal Cord Injury

Chen

Shi

et al. 2022

Front. Immunol.

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ObjectivesThis study aimed to evaluate the expression of cytosine monophosphate kinase 2 (CMPK2) and activation of the NLRP3 inflammasome in rats with spinal cord injury (SCI) and to characterize the effects of electroacupuncture on CMPK2-associated regulation of the NLRP3 inflammasome.MethodsAn SCI model was established in Sprague–Dawley (SD) rats. The expression levels of NLRP3 and CMPK2 were measured at different time points following induction of SCI. The rats were randomly divided into a sham group (Sham), a model group (Model), an electroacupuncture group (EA), an adeno-associated virus (AAV) CMPK2 group, and an AAV NC group. Electroacupuncture was performed at jiaji points on both sides of T9 and T11 for 20 min each day for 3 consecutive days. In the AAV CMPK2 and AAV NC groups, the viruses were injected into the T9 spinal cord via a microneedle using a microscope and a stereotactic syringe. The Basso–Beattie–Bresnahan (BBB) score was used to evaluate the motor function of rats in each group. Histopathological changes in spinal cord tissue were detected using H&E staining, and the expression levels of NLRP3, CMPK2, ASC, caspase-1, IL-18, and IL-1β were quantified using Western blotting (WB), immunofluorescence (IF), and RT-PCR.ResultsThe expression levels of NLRP3 and CMPK2 in the spinal cords of the model group were significantly increased at day 1 compared with those in the sham group (p < 0.05). The expression levels of NLRP3 and CMPK2 decreased gradually over time and remained low at 14 days post-SCI. We successfully constructed AAV CMPK2 and showed that CMPK2 was significantly knocked down following 2 dilutions. Finally, treatment with EA or AAV CMPK2 resulted in significantly increased BBB scores compared to those in the model group and the AAV NC group (p < 0.05). The histomorphology of the spinal cord in the EA and AAV CMPK2 groups was significantly different than that in the model and AAV NC groups. WB, IF, and PCR analyses showed that the expression levels of CMPK2, NLRP3, ASC, caspase-1, IL-18, and IL-1β were significantly lower in the EA and AAV CMPK2 groups compared with those in the model and AAV NC groups (p < 0.05).ConclusionOur study showed that CMPK2 regulated NLRP3 expression in rats with SCI. Activation of NLRP3 is a critical mechanism of inflammasome activation and the inflammatory response following SCI. Electroacupuncture downregulated the expression of CMPK2 and inhibited activation of NLRP3, which could improve motor function in rats with SCI.

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Pigment epithelium‑derived factor facilitates NLRP3 inflammasome activation through downregulating cytidine monophosphate kinase 2: A potential treatment strategy for missed abortion

Cited by 9 publications

References 34 publications

Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome‐Induced Pyroptosis via Inhibiting the TLR4/NF‐κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia

Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome‐Induced Pyroptosis via Inhibiting the TLR4/NF‐κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia

Clinical Efficacy and Safety Study of Mifepristone with Misoprostol Treatment in Patients with Missed Abortion

Electroacupuncture Inhibits NLRP3 Activation by Regulating CMPK2 After Spinal Cord Injury

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