Evidence and perspective for the role of the NLRP3 inflammasome signaling pathway in ischemic stroke and its therapeutic potential (Review)

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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Therapeutic STING activation boosts microglia phagocytosis and ameliorates depression-like behaviors during chronic restraint stress

10.21203/rs.3.rs-695179/v1 ◽

2021 ◽

Author(s):

Qian Zhai ◽

Yanpeng Zhang ◽

Shuwen Tan ◽

Jianyu Sun ◽

Mao Ye ◽

...

Keyword(s):

Signaling Pathway ◽

Restraint Stress ◽

Potential Role ◽

Therapeutic Potential ◽

Chronic Restraint Stress ◽

Expression Levels ◽

Cell Counts ◽

Latex Beads ◽

Plus Maze

Abstract Background The STING-TBK1-IRF3 signaling pathway involves in modulating host innate immunity, however, the potential role of STING signaling pathway in chronic restraint stress model has not been determined. The aim of this study is to explore the underlying role of STING signaling pathway in regulating neuroinflammation, as well as to evaluate the therapeutic potential of STING agonist during chronic restraint stress. Methods C57BL/6 mice were subject to 14-day intermittent restraint stress. Sucrose preference, elevated plus maze and tail suspension tests were measured in chronic restraint stress mice. Expression levels of proinflammatory cytokines were tested by QT-PCR and Luminex cytokine assays. The fluorescence-labeled latex beads, flow cytometry and CD68 positive cell counts were utilized to evaluate phagocytic abilities of microglia. Then, the ability of intracerebroventricular injection of STING agonist, 2’3-cGAMP, to reverse the depression-like behaviors and inflammatory cytokines was examined. Results We found that the expression levels of STING, p-TBK1, and p-IRF3 were remarkably decreased in chronic restraint stress mice, which was associated with decreased IFN-β secretion. Moreover, the STING agonist, 2’3-cGAMP, significantly alleviated the neuroinflammation and ameliorated depression-like behavior which depends on the functional STING activation. Furthermore, 2’3-cGAMP promoted microglia phagocytosis through cGAMP-STING-dependent IFN-β release, which was essential for recovery from neuroinflammation during chronic restraint stress. Conclusions These findings demonstrate that STING signaling pathway is a critical mediator in regulating microglia phagocytosis and may serve as a novel therapeutic target for chronic stress-related psychiatric diseases.

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The probable role and therapeutic potential of the PI3K/AKT signaling pathway in SARS-CoV-2 induced coagulopathy

Cellular & Molecular Biology Letters ◽

10.1186/s11658-022-00308-w ◽

2022 ◽

Vol 27 (1) ◽

Author(s):

Mohammad Rafi Khezri ◽

Reza Varzandeh ◽

Morteza Ghasemnejad-Berenji

Keyword(s):

Signaling Pathway ◽

Distress Syndrome ◽

Therapeutic Potential ◽

Coagulation Factors ◽

Akt Signaling ◽

Akt Signaling Pathway ◽

Current Review ◽

Probable Role ◽

Intracellular Pathway

AbstractCoronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is associated with a high mortality rate. The majority of deaths in this disease are caused by ARDS (acute respiratory distress syndrome) followed by cytokine storm and coagulation complications. Although alterations in the level of the number of coagulation factors have been detected in samples from COVID-19 patients, the direct molecular mechanism which has been involved in this pathologic process has not been explored yet. The PI3K/AKT signaling pathway is an intracellular pathway which plays a central role in cell survival. Also, in recent years the association between this pathway and coagulopathies has been well clarified. Therefore, based on the evidence on over-activity of the PI3K/AKT signaling pathway in SARS-CoV-2 infection, in the current review, the probable role of this cellular pathway as a therapeutic target for the prevention of coagulation complications in patients with COVID-19 is discussed.

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The Therapeutic Potential of MAPK/ERK Inhibitors in the Treatment of Colorectal Cancer

Current Cancer Drug Targets ◽

10.2174/1568009621666211103113339 ◽

2021 ◽

Vol 21 ◽

Author(s):

Mehran Pashirzad ◽

Reihaneh Khorasanian ◽

Maryam Mahmoudi Fard ◽

Mohammad-Hassan Arjmand ◽

Hadis Langari ◽

...

Keyword(s):

Colorectal Cancer ◽

Signaling Pathway ◽

Therapeutic Potential ◽

Current Knowledge ◽

Erk Signaling ◽

Clinical Settings ◽

Cancer Cell Proliferation ◽

Resistance Mutations ◽

Clinical Value

: The MAPK/ERK signaling pathway regulates cancer cell proliferation, apoptosis, inflammation, angiogenesis, metastasis and drug resistance. Mutations and up-regulation of components of the MAPK/ERK signaling pathway, as well as over-activation of this critical signaling pathway, are frequently observed in colorectal carcinomas. Targeting the MAPK/ERK signaling pathway, using specific pharmacological inhibitors, elicits potent anti-tumor effects, supporting the therapeutic potential of these inhibitors in the treatment of CRC. Several drugs have recently been developed for the inhibition of the MEK/ERK pathway in preclinical and clinical settings, such as MEK162 and MK-2206. MEK1/2 inhibitors demonstrate promising efficacy and anticancer activity for the treatment of this malignancy. This review summarizes the current knowledge on the role of the MAPK/ERK signaling pathway in the pathogenesis of CRC and the potential clinical value of synthetic inhibitors of this pathway in preventing CRC progression for a better understanding, and hence, better management of colorectal cancer.

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Role of fractalkine/CX3CR1 signaling pathway in the recovery of neurological function after early ischemic stroke in a rat model

Life Sciences ◽

10.1016/j.lfs.2017.06.012 ◽

2017 ◽

Vol 184 ◽

pp. 87-94 ◽

Cited By ~ 13

Author(s):

Yan-Zhi Liu ◽

Chun Wang ◽

Qian Wang ◽

Yong-Zhong Lin ◽

Yu-Song Ge ◽

...

Keyword(s):

Ischemic Stroke ◽

Signaling Pathway ◽

Rat Model ◽

Neurological Function

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CTRP13 Protects H9c2 Cells Against Hypoxia/Reoxygenation (H/R)-Induced Injury Via Regulating the AMPK/Nrf2/ARE Signaling Pathway

Cell Transplantation ◽

10.1177/09636897211033275 ◽

2021 ◽

Vol 30 ◽

pp. 096368972110332

Author(s):

Weifeng Jiang ◽

Jungang Song ◽

Suitao Zhang ◽

Yanyan Ye ◽

Jun Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Signaling Pathway ◽

Therapeutic Potential ◽

Ischemia Reperfusion ◽

Myocardial Necrosis ◽

Inhibitory Effect ◽

Protective Effects ◽

H9c2 Cells ◽

Hypoxia Reoxygenation

Myocardial infarction (MI) is identified as the myocardial necrosis due to myocardial ischemia/reperfusion (I/R) injury and remains a leading cause of mortality. C1q/TNF-related protein 13 (CTRP13) is a member of CTRP family that has been found to be involved in coronary artery disease (CAD). However, the role of CTRP13 in MI remains unclear. We aimed to explore the functional role of CTRP13 in H9c2 cells exposed to hypoxia/reoxygenation (H/R). Our results demonstrated that H/R stimulation significantly decreased the expression of CTRP13 in H9c2 cells. H/R-induced an increase in ROS production and reductions in activities of SOD and CAT were prevented by CTRP13 overexpression but were aggravated by CTRP13 silencing. Moreover, CTRP13 overexpression could reverse the inductive effect of H/R on caspase-3 activity and bax expression, as well as the inhibitory effect of H/R on bcl-2 expression in H9c2 cells. However, CTRP13 silencing presented opposite effects with CTRP13 overexpression. Furthermore, CTRP13 overexpression enhanced the H/R-stimulated the expression levels of p-AMPK and nuclear Nrf2, and Nrf2 transcriptional activity. However, inhibition of AMPK reversed the CTRP13-mediated activation of Nrf2/ARE signaling and the cardiac-protective effect in H/R-exposed H9c2 cells. Additionally, silencing of Nrf2 reversed the protective effects of CTRP13 against H/R-stimulated oxidative stress and apoptosis in H9c2 cells. Finally, recombinant CTRP13 protein attenuated myocardial I/R-induced injury in rats. Taken together, these findings indicated that CTRP13 protected H9c2 cells from H/R-stimulated oxidative stress and apoptosis via regulating the AMPK/Nrf2/ARE signaling pathway. Our results provided evidence for the therapeutic potential of CTRP13 in myocardial I/R injury.

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Targeting the NLRP3 Inflammasome as a New Therapeutic Option for Overcoming Cancer

Cancers ◽

10.3390/cancers13102297 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2297

Author(s):

Sonia Missiroli ◽

Mariasole Perrone ◽

Caterina Boncompagni ◽

Chiara Borghi ◽

Alberto Campagnaro ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Therapeutic Potential ◽

Therapeutic Option ◽

Anticancer Therapy ◽

New Drugs ◽

Inflammasome Activation ◽

Interleukin 18 ◽

Nlrp3 Inflammasome Activation ◽

Therapy Target

Inflammasomes are multiprotein complexes that regulate the maturation and secretion of the proinflammatory cytokines interleukin-1beta (IL-1βand interleukin-18 (IL-18) in response to various intracellular stimuli. As a member of the inflammasomes family, NLRP3 is the most studied and best characterized inflammasome and has been shown to be involved in several pathologies. Recent findings have made it increasingly apparent that the NLRP3 inflammasome may also play a central role in tumorigenesis, and it has attracted attention as a potential anticancer therapy target. In this review, we discuss the role of NLRP3 in the development and progression of cancer, offering a detailed summary of NLRP3 inflammasome activation (and inhibition) in the pathogenesis of various forms of cancer. Moreover, we focus on the therapeutic potential of targeting NLRP3 for cancer therapy, emphasizing how understanding NLRP3 inflammasome-dependent cancer mechanisms might guide the development of new drugs that target the inflammatory response of tumor-associated cells.

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Melatonin Attenuates Pyroptosis Upon Spinal Nerve Ligation in Rats via the NF-κB/NLRP3 Inflammasome Signaling Pathway

10.21203/rs.3.rs-221761/v1 ◽

2021 ◽

Author(s):

Yi-Hao Wang ◽

Xiao Gao ◽

Yu-Ru Tang ◽

Nan-Nan Zhang ◽

Zhao-Jun Liang ◽

...

Keyword(s):

Signaling Pathway ◽

Nlrp3 Inflammasome ◽

Spinal Nerve ◽

Spinal Nerve Ligation ◽

Potential Mechanism ◽

Behavioral Experiments ◽

Immune Mediated ◽

Pain Models ◽

Excessive Activation

Abstract Accumulated evidences have demonstrated causative links between neuropathic pain (NP) and immune-mediated inflammatory disorders. However, the role of inflammasome-induced pyroptosis in NP remains elusive. Melatonin possesses a well-documented analgesic action in various pain models. A rat model of spinal nerve ligation was established to explore the potential mechanism of melatonin in pyroptosis. The current study aimed to test our hypothesis that melatonin regulated pyroptosis to alleviate NP by inhibiting NF-κB/NLRP3-dependent signaling. Behavioral experiments revealed that SNL provoked severe allodynia which were suppressed by the administration of melatonin, caspase-1 inhibitor (VX-765) or NF-κB inhibitor (BAY 11-7085). SNL significantly up-regulated the inflammatory cytokines associated with the excessive activation of NLRP3 components and NF-κB signaling, as well as the marked pyroptosis activation which were partially inhibited by melatonin, VX-765 or BAY 11-7085. Collectively, Melatonin has potent analgesic and anti-inflammatory effects in SNL models through preventing pyroptosis via the NF-κB/NLRP3 inflammasome signaling pathway.

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