Research

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18 pages, 2800 KiB

Open AccessArticle

Inflammatory Biomarkers of Traumatic Brain Injury

by Nathan H. Johnson, Roey Hadad, Ruby Rose Taylor, Javier Rodríguez Pilar, Osman Salazar, Juan Antonio Llompart-Pou, W. Dalton Dietrich, Robert W. Keane, Jon Pérez-Bárcena and Juan Pablo de Rivero Vaccari

Pharmaceuticals 2022, 15(6), 660; https://doi.org/10.3390/ph15060660 - 25 May 2022

Cited by 12 | Viewed by 2565

Abstract

Traumatic brain injury (TBI) has a complex pathology in which the initial injury releases damage associated proteins that exacerbate the neuroinflammatory response during the chronic secondary injury period. One of the major pathological players in the inflammatory response after TBI is the inflammasome. [...] Read more.

Traumatic brain injury (TBI) has a complex pathology in which the initial injury releases damage associated proteins that exacerbate the neuroinflammatory response during the chronic secondary injury period. One of the major pathological players in the inflammatory response after TBI is the inflammasome. Increased levels of inflammasome proteins during the acute phase after TBI are associated with worse functional outcomes. Previous studies reveal that the level of inflammasome proteins in biological fluids may be used as promising new biomarkers for the determination of TBI functional outcomes. In this study, we provide further evidence that inflammatory cytokines and inflammasome proteins in serum may be used to determine injury severity and predict pathological outcomes. In this study, we analyzed blood serum from TBI patients and respective controls utilizing Simple Plex inflammasome and V-PLEX inflammatory cytokine assays. We performed statistical analyses to determine which proteins were significantly elevated in TBI individuals. The receiver operating characteristics (ROC) were determined to obtain the area under the curve (AUC) to establish the potential fit as a biomarker. Potential biomarkers were then compared to documented patient Glasgow coma scale scores via a correlation matrix and a multivariate linear regression to determine how respective biomarkers are related to the injury severity and pathological outcome. Inflammasome proteins and inflammatory cytokines were elevated after TBI, and the apoptosis-associated speck like protein containing a caspase recruitment domain (ASC), interleukin (IL)-18, tumor necrosis factor (TNF)-α, IL-4 and IL-6 were the most reliable biomarkers. Additionally, levels of these proteins were correlated with known clinical indicators of pathological outcome, such as the Glasgow coma scale (GCS). Our results show that inflammatory cytokines and inflammasome proteins are promising biomarkers for determining pathological outcomes after TBI. Additionally, levels of biomarkers could potentially be utilized to determine a patient’s injury severity and subsequent pathological outcome. These findings show that inflammation-associated proteins in the blood are reliable biomarkers of injury severity that can also be used to assess the functional outcomes of TBI patients. Full article

(This article belongs to the Special Issue Molecular Mechanism of Inflammasome Activation: Implications in Physiological and Pathological Conditions)

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18 pages, 2266 KiB

Open AccessArticle

Downstream Signaling of Inflammasome Pathway Affects Patients’ Outcome in the Context of Distinct Molecular Breast Cancer Subtypes

by Concetta Saponaro, Annarita Fanizzi, Margherita Sonnessa, Paolo Mondelli, Daniele Vergara, Donato Loisi, Raffaella Massafra, Agnese Latorre, Francesco A. Zito and Laura Schirosi

Pharmaceuticals 2022, 15(6), 651; https://doi.org/10.3390/ph15060651 - 24 May 2022

Cited by 4 | Viewed by 1641

Abstract

Inflammasomes are protein complexes involved in the regulation of different biological conditions. Over the past few years, the role of NLRP3 in different tumor types has gained interest. In breast cancer (BC), NLRP3 has been associated with multiple processes including epithelia mesenchymal transition, [...] Read more.

Inflammasomes are protein complexes involved in the regulation of different biological conditions. Over the past few years, the role of NLRP3 in different tumor types has gained interest. In breast cancer (BC), NLRP3 has been associated with multiple processes including epithelia mesenchymal transition, invasion and metastization. Little is known about molecular modifications of NLRP3 up-regulation. In this study, in a cohort of BCs, the expression levels of NLRP3 and PYCARD were analyzed in combination with CyclinD1 and MYC ones and their gene alterations. We described a correlation between the NLRP3/PYCARD axis and CyclinD1 (p < 0.0001). NLRP3, PYCARD and CyclinD1’s positive expression was observed in estrogen receptor (ER) and progesterone receptor (PgR) positive cases (p < 0.0001). Furthermore, a reduction of NLRP3 and PYCARD expression has been observed in triple negative breast cancers (TNBCs) with respect to the Luminal phenotypes (p = 0.017 and p = 0.0015, respectively). The association NLRP3+/CCND1+ or PYCARD+/CCND1+ was related to more aggressive clinicopathological characteristics and a worse clinical outcome, both for progression free survival (PFS) and overall survival (OS) with respect to NLRP3+/CCND1− or PYCARD+/CCND1− patients, both in the whole cohort and also in the subset of Luminal tumors. In conclusion, our study shows that the NLRP3 inflammasome complex is down-regulated in TNBC compared to the Luminal subgroup. Moreover, the expression levels of NLRP3 and PYCARD together with the alterations of CCND1 results in Luminal subtype BC’ss poor prognosis. Full article

(This article belongs to the Special Issue Molecular Mechanism of Inflammasome Activation: Implications in Physiological and Pathological Conditions)

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11 pages, 886 KiB

Open AccessArticle

Pharmacological and Epigenetic Regulators of NLRP3 Inflammasome Activation in Alzheimer’s Disease

by Francesca La Rosa, Roberta Mancuso, Simone Agostini, Federica Piancone, Ivana Marventano, Marina Saresella, Ambra Hernis, Chiara Fenoglio, Daniela Galimberti, Elio Scarpini and Mario Clerici

Pharmaceuticals 2021, 14(11), 1187; https://doi.org/10.3390/ph14111187 - 20 Nov 2021

Cited by 14 | Viewed by 2358

Abstract

Activation of the NLRP3 inflammasome complex results in the production of IL-18, Caspase-1 and IL-1β. These cytokines have a beneficial role in promoting inflammation, but an excessive activation of the inflammasome and the consequent constitutive inflammatory status is a negative factor in human [...] Read more.

Activation of the NLRP3 inflammasome complex results in the production of IL-18, Caspase-1 and IL-1β. These cytokines have a beneficial role in promoting inflammation, but an excessive activation of the inflammasome and the consequent constitutive inflammatory status is a negative factor in human pathologies including Alzheimer’s Disease (AD). MicroRNAs (miR-NAs) target the 3′UTR region of NLRP3, preventing the activation of the inflammasome and inhibiting cytokine production. Because Stavudine (D4T), an antiretroviral drug, was recently shown to reduce inflammasome activation, we verified whether its effect is mediated by miR-7-5p, miR-22-3p, miR-30e-5p and miR-223-3p: miRNAs that bind the NLRP3-mRNA-UTR region and interfere with protein translation, reducing NLRP3 activation. Peripheral blood mononuclear cells (PBMCs) of twenty AD patients and ten sex-matched Healthy Controls (HC) were stimulated with Lipopolysaccharides (LPS)+Amyloid-beta (Aβ₄₂) in the absence/presence of D4T. Expression of genes within the inflammasome complex and of miRNAs was evaluated by RT-PCR; cytokines and caspase-1 production was measured by ELISA. Results have shown that: NLRP3, ASC, IL-1β and IL-18 expression, as well as IL-18, IL-1β and caspase-1 production, were significantly augmented (p < 0.05) in LPS+Aβ₄₂-stimulated PBMCs of AD patients compared to HC. D4T reduced the expression of inflammasome genes and cytokine production (p < 0.005). miR-7-5p and miR-223-3p expression was significantly increased in LPS+Aβ₄₂-stimulated PBMCs of AD patients (p < 0.05), and it was reduced by D4T in AD alone. In conclusion: miR-223-3p and mir-7-5p expression is increased in AD, but this does not result in down-regulation of NLRP3 inflammasome expression and of IL-1β and IL-18 production. D4T increased miRNA expression in HC but had an opposite effect in AD, suggesting that miRNA regulatory mechanisms are altered in AD. Full article

(This article belongs to the Special Issue Molecular Mechanism of Inflammasome Activation: Implications in Physiological and Pathological Conditions)

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15 pages, 4484 KiB

Open AccessArticle

Endothelial Thioredoxin-Interacting Protein Depletion Reduces Hemorrhagic Transformation in Hyperglycemic Mice after Embolic Stroke and Thrombolytic Therapy

by Mohd. Salman, Saifudeen Ismael, Lexiao Li, Heba A. Ahmed, Michelle A. Puchowicz and Tauheed Ishrat

Pharmaceuticals 2021, 14(10), 983; https://doi.org/10.3390/ph14100983 - 27 Sep 2021

Cited by 3 | Viewed by 1917

Abstract

We hypothesize that endothelial-specific thioredoxin-interacting protein knock-out (EC-TXNIP KO) mice will be more resistant to the neurovascular damage (hemorrhagic-transformation-HT) associated with hyperglycemia (HG) in embolic stroke. Adult-male EC-TXNIP KO and wild-type (WT) littermate mice were injected with-streptozotocin (40 mg/kg, i.p.) for five consecutive [...] Read more.

We hypothesize that endothelial-specific thioredoxin-interacting protein knock-out (EC-TXNIP KO) mice will be more resistant to the neurovascular damage (hemorrhagic-transformation-HT) associated with hyperglycemia (HG) in embolic stroke. Adult-male EC-TXNIP KO and wild-type (WT) littermate mice were injected with-streptozotocin (40 mg/kg, i.p.) for five consecutive days to induce diabetes. Four-weeks after confirming HG, mice were subjected to embolic middle cerebral artery occlusion (eMCAO) followed by tissue plasminogen activator (tPA)-reperfusion (10 mg/kg at 3 h post-eMCAO). After the neurological assessment, animals were sacrificed at 24 h for neurovascular stroke outcomes. There were no differences in cerebrovascular anatomy between the strains. Infarct size, edema, and HT as indicated by hemoglobin (Hb)-the content was significantly higher in HG-WT mice, with or without tPA-reperfusion, compared to normoglycemic WT mice. Hyperglycemic EC-TXNIP KO mice treated with tPA tended to show lower Hb-content, edema, infarct area, and less hemorrhagic score compared to WT hyperglycemic mice. EC-TXNIP KO mice showed decreased expression of inflammatory mediators, apoptosis-associated proteins, and nitrotyrosine levels. Further, vascular endothelial growth factor-A and matrix-metalloproteinases (MMP-9/MMP-3), which degrade junction proteins and increase blood-brain-barrier permeability, were decreased in EC-TXNIP KO mice. Together, these findings suggest that vascular-TXNIP could be a novel therapeutic target for neurovascular damage after stroke. Full article

(This article belongs to the Special Issue Molecular Mechanism of Inflammasome Activation: Implications in Physiological and Pathological Conditions)

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13 pages, 2209 KiB

Open AccessArticle

Doxycycline Attenuates Cancer Cell Growth by Suppressing NLRP3-Mediated Inflammation

by Mohammad Alsaadi, Gulcin Tezcan, Ekaterina E. Garanina, Shaimaa Hamza, Alan McIntyre, Albert A. Rizvanov and Svetlana F. Khaiboullina

Pharmaceuticals 2021, 14(9), 852; https://doi.org/10.3390/ph14090852 - 26 Aug 2021

Cited by 14 | Viewed by 6177

Abstract

NLR family pyrin domain containing 3 (NLRP3) inflammasome formation is triggered by the damaged mitochondria releasing reactive oxygen species. Doxycycline was shown to regulate inflammation; however, its effect on NLRP3 in cancer remains largely unknown. Therefore, we sought to determine the effect of [...] Read more.

NLR family pyrin domain containing 3 (NLRP3) inflammasome formation is triggered by the damaged mitochondria releasing reactive oxygen species. Doxycycline was shown to regulate inflammation; however, its effect on NLRP3 in cancer remains largely unknown. Therefore, we sought to determine the effect of doxycycline on NLRP3 regulation in cancer using an in vitro model. NLRP3 was activated in a prostate cancer cell line (PC3) and a lung cancer cell line (A549) before treatment with doxycycline. Inflammasome activation was assessed by analyzing RNA expression of NLRP3, Pro-CASP-1, and Pro-IL1β using RT-qPCR. Additionally, NLPR3 protein expression and IL-1β secretion were analyzed using Western blot and ELISA, respectively. Tumor cell viability was determined using Annexin V staining and a cell proliferation assay. Cytokine secretion was analyzed using a 41Plex assay for human cytokines. Data were analyzed using one-way ANOVA model with Tukey’s post hoc tests. Doxycycline treatment decreased NLRP3 formation in PC3 and A549 cells compared to untreated and LPS only treated cells (p < 0.05). Doxycycline also decreased proliferation and caused cell death through apoptosis, a response that differed to the LPS-Nigericin mediated pyroptosis. Our findings suggest that doxycycline inhibits LPS priming of NLRP3 and reduces tumor progression through early apoptosis in cancer. Full article

(This article belongs to the Special Issue Molecular Mechanism of Inflammasome Activation: Implications in Physiological and Pathological Conditions)

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14 pages, 4697 KiB

Open AccessArticle

Protective Effect of Piplartine against LPS-Induced Sepsis through Attenuating the MAPKs/NF-κB Signaling Pathway and NLRP3 Inflammasome Activation

by Chi-Han Huang, Shu-Chi Wang, I-Chen Chen, Yi-Ting Chen, Po-Len Liu, Shih-Hua Fang, Shu-Pin Huang, Hsin-Chih Yeh, Ching-Chih Liu, Po-Yen Lee, Tzu-Chieh Lin, Wei-Chung Cheng, Chia-Cheng Su, Hsin-En Wu, Yuan-Ru Chen and Chia-Yang Li

Pharmaceuticals 2021, 14(6), 588; https://doi.org/10.3390/ph14060588 - 18 Jun 2021

Cited by 20 | Viewed by 3772

Abstract

Piplartine (or Piperlongumine) is a natural alkaloid isolated from Piper longum L., which has been proposed to exhibit various biological properties such as anti-inflammatory effects; however, the effect of piplartine on sepsis has not been examined. This study was performed to examine the [...] Read more.

Piplartine (or Piperlongumine) is a natural alkaloid isolated from Piper longum L., which has been proposed to exhibit various biological properties such as anti-inflammatory effects; however, the effect of piplartine on sepsis has not been examined. This study was performed to examine the anti-inflammatory activities of piplartine in vitro, ex vivo and in vivo using murine J774A.1 macrophage cell line, peritoneal macrophages, bone marrow-derived macrophages and an animal sepsis model. The results demonstrated that piplartine suppresses iNOS and COX-2 expression, reduces PGE₂, TNF-α and IL-6 production, decreases the phosphorylation of MAPKs and NF-κB and attenuates NF-κB activity by LPS-activated macrophages. Piplartine also inhibits IL-1β production and suppresses NLRP3 inflammasome activation by LPS/ATP- and LPS/nigericin-activated macrophages. Moreover, piplartine reduces the production of nitric oxide (NO) and TNF-α, IL-6 and IL-1β, decreases LPS-induced tissue damage, attenuates infiltration of inflammatory cells and enhances the survival rate. Collectively, these results demonstrate piplartine exhibits anti-inflammatory activities in LPS-induced inflammation and sepsis and suggest that piplartine might have benefits for sepsis treatment. Full article

(This article belongs to the Special Issue Molecular Mechanism of Inflammasome Activation: Implications in Physiological and Pathological Conditions)

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Review

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27 pages, 1600 KiB

Open AccessReview

Molecular Mechanisms of Inflammasome in Ischemic Stroke Pathogenesis

by Maria Grazia Puleo, Salvatore Miceli, Tiziana Di Chiara, Giuseppina Maria Pizzo, Vittoriano Della Corte, Irene Simonetta, Antonio Pinto and Antonino Tuttolomondo

Pharmaceuticals 2022, 15(10), 1168; https://doi.org/10.3390/ph15101168 - 21 Sep 2022

Cited by 12 | Viewed by 2118

Abstract

Ischemic stroke (also called cerebral ischemia) is one of the leading causes of death and severe disability worldwide. NLR inflammasomes play a crucial role in sensing cell damage in response to a harmful stimuli and modulating the inflammatory response, promoting the release of [...] Read more.

Ischemic stroke (also called cerebral ischemia) is one of the leading causes of death and severe disability worldwide. NLR inflammasomes play a crucial role in sensing cell damage in response to a harmful stimuli and modulating the inflammatory response, promoting the release of pro-inflammatory cytokines such as IL-18 and IL-1β following ischemic injury. Therefore, a neuroprotective effect is achieved by inhibiting the expression, assembly, and secretion of inflammasomes, thus limiting the extent of brain detriment and neurological sequelae. This review aims to illustrate the molecular characteristics, expression levels, and assembly of NLRP3 (nucleotide-binding oligomerization domain-like receptor [NLR] family pyrin-domain-containing 3) inflammasome, the most studied in the literature, in order to discover promising therapeutic implications. In addition, we provide some information regarding the contribution of NLRP1, NLRP2, and NLRC4 inflammasomes to ischemic stroke pathogenesis, highlighting potential therapeutic strategies that require further study. Full article

(This article belongs to the Special Issue Molecular Mechanism of Inflammasome Activation: Implications in Physiological and Pathological Conditions)

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23 pages, 2463 KiB

Open AccessReview

Contribution of Mitochondrial Dysfunction Combined with NLRP3 Inflammasome Activation in Selected Neurodegenerative Diseases

by Anna Litwiniuk, Agnieszka Baranowska-Bik, Anita Domańska, Małgorzata Kalisz and Wojciech Bik

Pharmaceuticals 2021, 14(12), 1221; https://doi.org/10.3390/ph14121221 - 25 Nov 2021

Cited by 13 | Viewed by 2642

Abstract

Alzheimer’s disease and Parkinson’s disease are the most common forms of neurodegenerative illnesses. It has been widely accepted that neuroinflammation is the key pathogenic mechanism in neurodegeneration. Both mitochondrial dysfunction and enhanced NLRP3 (nucleotide-binding oligomerization domain (NOD)-like receptor protein 3) inflammasome complex activity [...] Read more.

Alzheimer’s disease and Parkinson’s disease are the most common forms of neurodegenerative illnesses. It has been widely accepted that neuroinflammation is the key pathogenic mechanism in neurodegeneration. Both mitochondrial dysfunction and enhanced NLRP3 (nucleotide-binding oligomerization domain (NOD)-like receptor protein 3) inflammasome complex activity have a crucial role in inducing and sustaining neuroinflammation. In addition, mitochondrial-related inflammatory factors could drive the formation of inflammasome complexes, which are responsible for the activation, maturation, and release of pro-inflammatory cytokines, including interleukin-1β (IL-1β) and interleukin-18 (IL-18). The present review includes a broadened approach to the role of mitochondrial dysfunction resulting in abnormal NLRP3 activation in selected neurodegenerative diseases. Moreover, we also discuss the potential mitochondria-focused treatments that could influence the NLRP3 complex. Full article

(This article belongs to the Special Issue Molecular Mechanism of Inflammasome Activation: Implications in Physiological and Pathological Conditions)

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