REVIEW | doi:10.20944/preprints201904.0208.v1
Subject: Medicine And Pharmacology, Pathology And Pathobiology Keywords: rhabdomyolysis; pigment nephropathy; haem; NLRP3 inflammasome; acute kidney injury
Online: 18 April 2019 (08:11:08 CEST)
Pigment nephropathy is an acute decline in renal function following the deposition of endogenous haem-containing proteins in the kidneys. Haem pigments such as myoglobin and haemoglobin are filtered by glomeruli and absorbed by the proximal tubules. They cause renal vasoconstriction, tubular obstruction, increased oxidative stress and inflammation. Haem is associated with inflammation in sterile and infectious conditions, contributing to the pathogenesis of many disorders such as rhabdomyolysis and haemolytic diseases. In fact, haem appears to be a signaling molecule that is able to activate the inflammasome pathway. Recent studies highlight a pathogenic function for haem in triggering inflammatory responses through the activation of the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome. Among the inflammasome multiprotein complexes, the NLRP3 inflammasome has been the most widely characterized as a trigger of inflammatory caspases and the maturation of interleukin-18 and -1β. In the present review, we discuss the latest evidence on the importance of inflammasome-mediated inflammation in pigment nephropathy. Finally, we highlight the potential role of inflammasome inhibitors in the prophylaxis and treatment of pigment nephropathy.
ARTICLE | doi:10.20944/preprints202102.0112.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: cell cycle; cell synchronization; pro-inflammatory cytokines; Anaphase promoting complex subunit 10, Anapc10; Anaphase-promoting complex/cyclosome, APC/C; PYRIN domain containing-3, NLRP3; The NLRP3 inflammasome
Online: 3 February 2021 (10:32:38 CET)
Activation of the NLRP3 inflammasome plays a crucial role in innate immune response. During cell division, the NLRP3 inflammasome activation must be strictly controlled. Here, we discovered the anaphase promoting complex subunit 10 (Anapc10, APC10), a substrate recognition protein of the anaphase promoting complex/cyclosome (APC/C), is a critical mediator of the NLRP3 inflammasome activation. APC10 protein interacts with NLRP3, and co-localizes with NLRP3 protein in the cytoplasm. During interphase, APC10 interacts with NLRP3 to promote the NLRP3 inflammasome activation. During mitosis, APC10 disassociates from the NLRP3 inflammasome to inhibit the inflammatory responses. This study reveals a distinct mechanism by which APC10 serves as a switch of the NLRP3 inflammasome activation during cell cycle.
REVIEW | doi:10.20944/preprints202005.0357.v1
Subject: Medicine And Pharmacology, Obstetrics And Gynaecology Keywords: NLRP3; inflammation; preeclampsia; pregnancy induced hypertension; HELLP syndrome; immunothrombosis
Online: 23 May 2020 (05:15:54 CEST)
Pregnancy-induced hypertension and preeclampsia are associated with significant maternal and fetal mortality. A better understanding of those diseases, delineation of molecular pathomechanism, and efficient treatment development are some of the most urgent tasks in obstetrics and gynecology. Recent findings indicate a crucial role of inflammation in the development of hypertension and preeclampsia. Although the mechanism is very complex and needs further explanation, it appears that high levels of cholesterol, urate, and glucose activates NLRP3 inflammasome, which produces IL-1β, IL-18 and gasdermin D. Production of these proinflammatory chemokines is a beginning of local and general inflammation, what results in sympathetic outflow, angiotensin II production, proteinuria, hemolysis, liver damage, immunothrombosis, and coagulopathy. NLRP3 inflammasome is a critical complex in the mediation of inflammatory response, which makes it crucial for the development of pregnancy-induced hypertension and preeclampsia, as well as its complications, such as placental abruption and HELLP syndrome. Herein presented the article delineate molecular mechanisms of those processes, indicating directions of future advance.
REVIEW | doi:10.20944/preprints202304.0516.v1
Subject: Medicine And Pharmacology, Internal Medicine Keywords: SGLT-2 Inhibitors; Inflammasome; NLRP3; reno-protective effects; Cardio-protective effects; neuro-protective effects.
Online: 18 April 2023 (10:33:39 CEST)
Nucleotide-binding domain like receptor protein 3 (NLRP3) inflammasome in the kidney and the heart is increasingly being suggested to play a key role in mediating inflammation. In the kidney, NLRP3 activation has been associated with the progression of diabetic kidney disease. In the heart, activation of the NLRP3 inflammasome has been related to enhanced release of interleukin-1β (IL-1β) and the subsequent induction of atherosclerosis and heart failure. Apart from their glucose-lowering effects, SGLT-2 Inhibitors have been documented to attenuate activation of the NLRP3, thus, resulting in the constellation of an anti-inflammatory milieu. In this review, we will focus on the interplay between SGLT-2 Inhibitors and the inflammasome in the kidney, the heart and the neurons in the context of diabetes mellitus and its complications.
ARTICLE | doi:10.20944/preprints202204.0077.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Delta-9-tetrahydrocannabinol; cannabidiol; cannabinoids; NLRP3 inflammasome; STAT3; TYK2; cytokine storm; interleukins; TNF-α; macrophages; primary lung bronchial epithelial cells
Online: 8 April 2022 (08:51:26 CEST)
Cannabinoids, mainly cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), are the most studied group of compounds obtained from Cannabis sativa because of their several pharmaceutical properties. Current evidence suggests a crucial role of cannabinoids as potent anti-inflammatory agents for the treatment of chronic inflammatory diseases; however, the mechanisms remain largely unclear. Cytokine storm, a dysregulated severe inflammatory response by our immune system, is involved in the pathogenesis of numerous chronic inflammatory disorders, including coronavirus disease 2019 (COVID-19), which results in the accumulation of pro-inflammatory cytokines. Therefore, we hypothesized that CBD and THC reduce the levels of pro-inflammatory cytokines by inhibiting key inflammatory signalling pathways. The nucleotide-binding and oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome signalling has been implicated in a variety of chronic inflammatory diseases, which results in the release of pyroptotic cytokines, interleukin-1β (IL-1β) and IL-18. Likewise, the activation of the signal transducer and activator of transcription-3 (STAT3) causes increased expression of pro-inflammatory cytokines. We studied the effects of CBD and THC on lipopolysaccharide (LPS)-induced inflammatory response in human THP-1 macrophages and primary human bronchial epithelial cells (HBECs). Our results revealed that CBD and, for the first time, THC, significantly inhibited NLRP3 inflammasome activation following LPS + ATP stimulation, leading to a reduction in the levels of IL-1β in THP-1 macrophages and HBECs. CBD attenuated the phosphorylation of nuclear factor-κB (NF-κB) and both cannabinoids inhibited the generation of oxidative stress post-LPS. Our multiplex ELISA data revealed that CBD and THC significantly diminished the levels of IL-6, IL-8, and tumor necrosis factor-α (TNF-α) after LPS treatment in THP-1 macrophages and HBECs. In addition, the phosphorylation of STAT3 was significantly downregulated by CBD and THC in THP-1 macrophages and HBECs, which was in turn, attributed to the reduced phosphorylation of tyrosine kinase-2 (TYK2) by CBD and THC after LPS stimulation in these cells. Overall, CBD and THC were found to be effective in alleviating the LPS-induced cytokine storm in human macrophages and primary HBECs, at least via modulation of NLRP3 inflammasome and STAT3 signalling pathways. The encouraging results from this study warrant further investigation of these cannabinoids in vivo.
REVIEW | doi:10.20944/preprints202301.0416.v1
Subject: Medicine And Pharmacology, Dentistry And Oral Surgery Keywords: Inflammasome; NLRP3; periodontal disease; periodontal pathogen; IL-1β
Online: 23 January 2023 (15:07:31 CET)
Dr. Jurg Tschopp created the word "inflammasome" in 2002. Inflammasome activation and its function in disease processes have been the subject of significant investigation over the last 15 years. Four important inflammasomes have been identified: NLRP1, NLRP3, NLRC4, and AIM2. When these inflammasomes are activated, they process and secrete inflammatory cytokines such as IL-1b and IL-18, as well as cause pyroptosis, an inflammatory form of cell death. In this review, we will look at how these inflammasomes have been connected to Periodontitis pathogenesis.
ARTICLE | doi:10.20944/preprints202207.0067.v1
Subject: Medicine And Pharmacology, Cardiac And Cardiovascular Systems Keywords: restenosis; foam cells; NLRP3 inflammasome; MAPK signaling pathway
Online: 5 July 2022 (08:15:38 CEST)
The accumulation of foam cells in arterial intima and the accompanied chronic inflammation are considered major causes of neoatherosclerosis and restenosis. However, both the underlying mechanism and effective treatment for the disease are yet to be uncovered. In this study, we combined transcriptome profiling of restenosis artery tissue and bioinformatic analysis to reveal that NLRP3 inflammasome is markedly upregulated in restenosis and that several restenosis re-lated DEGs are also targets of mulberry extract, a natural dietary supplement used in traditional Chinese medicine to improve liver vitality. Further pathway enrichment analysis identified MAPK signaling pathway to be involved in the inflammatory response of foam cells. Consistently, immunofluorescence microscopy shows co-localization of NLRP3 with CD68+ macrophages. We then evaluated the efficacy of mulberry extract in inhibiting both the formation of foam cells and their inflammatory response. We demonstrated that mulberry extract suppresses the formation of ox-LDL induced foam cells, possibly by upregulating the cholesterol efflux genes ABCA1 and ABCG1 to inhibit intracellular lipid accumulation. In addition, mulberry extract dampens NLRP3 inflammasome activation by stressing the MAPK signaling pathway. Collectively, our mecha-nistic and functional studies unveil the therapeutic value of mulberry extract in neoatherosclerosis and restenosis treatment by regulating lipid metabolism and inflammatory response of foam cells.
REVIEW | doi:10.20944/preprints202205.0269.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: inflammation; calcium-sensing receptor; burns; chemokines; NLRP3 inflammasome
Online: 20 May 2022 (04:01:33 CEST)
Burn injury serves as an example of a condition with a robust inflammatory response. The elevation of circulating interleukins (IL)- 1 beta and -6 in children with severe burn injury up-regulate the parathyroid calcium sensing receptor (CaSR) resulting in hypocalcemic hypoparathyroidism with urinary calcium wasting. This effect protects the body from the hypercalcemia resulting from bone resorption liberating calcium into the circulation. Extracellular calcium can exacerbate and prolong the inflammatory response by stimulating mononuclear cell chemokine production as well as the NLRP3 inflammasome of the innate immune system, resulting in increased IL-1 production by monocytes and macrophages. Interestingly, the CaSR response to inflammatory cytokines disappears with age, potentially trapping calcium from bone resorption in the circulation and allowing it to contribute to increased inflammation and possibly increased calcium deposition in small arteries, , such as the coronaries, as conditions with increased chronic inflammation, such as spinal cord injury, osteoarthritis and rheumatoid arthritis have an incidence of cardiovascular disease and coronary artery calcium deposition significantly higher than the unaffected age-matched population.
Subject: Medicine And Pharmacology, Dietetics And Nutrition Keywords: Andrographis paniculata; 14-deoxy-11,12-didehydroandrographolide; NLRP3 inflammasome; liver injury; steatohepatitis
Online: 16 January 2020 (03:07:25 CET)
14-Deoxy-11,12-didehydroandrographolide (deAND), a diterpenoid in Andrographis paniculata (Burm. f.) Nees, acts as a bioactive phytonutrient that can treat many diseases. To investigate the protective effects of deAND on reducing fatty liver disease, male mice were fed a high-fat and high-cholesterol (HFHC) diet without or with 0.05% and 0.1% deAND supplementation. Cholesterol accumulation, antioxidant and anti-inflammatory activities in liver and liver injury were evaluated after deAND treatment. The results show that deAND treatment for 7 weeks reduced plasma alanine aminotransferase activity and lowered hepatic cholesterol accumulation, tumor nuclear factor-α, and histological lesions. 0.1% deAND treatment reduced HFHC diet-induced apoptosis by lowering the caspase 3/pro-caspase 3 ratio. After 11-weeks of deAND treatment, increased NOD-like receptor protein 3 (NLRP3), capase-1, and interleukin-1β protein levels in liver were suppressed by deAND treatment. In addition, nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA expression, heme oxygenase-1 protein expression, and the activities of glutathione peroxidase and glutathione reductase were increased in mice fed the HFHC diet. However, those activities of antioxidant enzymes or proteins were also upregulated by 0.1% deAND treatment. Furthermore, deAND treatment tended to lower hepatic lipid peroxides. Finally, deAND treatment reversed the depletion of hepatic glutamate level induced by HFHC diet. These results indicate that deAND may ameliorate HFHC diet-induced steatohepatitis and liver injury by increasing antioxidant and anti-inflammatory activities.
REVIEW | doi:10.20944/preprints202305.0829.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Acute Respiratory Distress Syndrome; COVID-19; Computed Tomography; Hormesis; Ionizing radiation; NLRP3 inflammasome
Online: 11 May 2023 (08:50:49 CEST)
United Nations Scientific Committee on the Effects of 2006 report was the first document released by an abandoned the classical paradigm that ionizing suppressive, considering the idea that at low doses enhances the appearance of antiinflammatory biomarkers [UNSCEAR 2006]. It considers energetic an immune modulation agent due to the multitude the innate immune system, depending on various age, health status, co-morbidities, genetic background, co-stressors [Lumniczky et al.]. Natural background radiation is the most hazardous public health, followed by medical imaging as a close Naturally occurring radionuclides attach to particulate ionizing radiation after inhalation and deposition in the in this article that exposure to particle radioactivity of inflammation. With that purpose, we have done an on common anti-inflammatory biomarkers between cases on COVID-19 elderly patients, and those found low-intensity natural ionizing radiation in locations with hypothesize that radioactivity increases biomarkers of strategy involved the use of databases from PubMed, (e.g., dose response, hormesis, J-shaped, NLRP3 LNT model, etc.). Extrapolating these effects to artificial ionizing radiation drawn conclusions on the over use of X-ray computed images in elderly ICU admitted patients with pulmonary oxygen species (ROS) generation by this action seems inflammation of leucine-rich protein 3 (NLRP3) inflammasome, waking up an over cytokine production.
REVIEW | doi:10.20944/preprints202010.0482.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Inflammasome; NF-κB; IRF; NLRP3; caspase-1; epigenetic modification; transcription factor; chromatin; promoter; enhancer
Online: 23 October 2020 (10:41:25 CEST)
Inflammasomes are multimolecular complexes with potent inflammatory activity. As such, their activity is tightly regulated at the transcriptional and post-transcriptional levels. In this review, we present the transcriptional regulation of inflammasome genes from sensors (e.g NLRP3) to substrates (e.g. IL-1β). Lineage-determining transcription factors shape inflammasome responses in different cell types with profound consequences on the responsiveness to inflammasome-activating stimuli. Pro-inflammatory signals (sterile or microbial) have a key transcriptional impact on inflammasome genes, which is largely mediated by NF-κB and, that translates into higher antimicrobial immune responses. Furthermore, diverse intrinsic (e.g. circadian clock, metabolites) or extrinsic (e.g. xenobiotics) signals are integrated by signal-dependent transcription factors and chromatin structure changes to modulate transcriptionally inflammasome responses. Finally, anti-inflammatory signals (e.g. IL-10) counterbalance inflammasome genes induction to limit deleterious inflammation. Transcriptional regulations thus appear as the first line of inflammasome regulation to raise the defense level in front of stress and infections but also to limit excessive or chronic inflammation.
REVIEW | doi:10.20944/preprints201702.0047.v1
Subject: Medicine And Pharmacology, Dietetics And Nutrition Keywords: advanced glycation end products; fructose; glucose; lipogenesis; sphingolipids; NLRP3; Nrf2; mitochondrial dysfunction; oxidative stress
Online: 14 February 2017 (08:38:14 CET)
The rapid increase in metabolic diseases occurred in the last three decades in both industrialized and developing countries has been related to the rise in sugar-added foods and sweetened beverages consumption. An emerging topic in the pathogenesis of metabolic diseases related to modern nutrition is the role of Advanced Glycation Endproducts (AGEs). AGEs can be ingested with high temperature processed foods, but also endogenously formed as consequence of a high dietary sugars intake. Animal models of high sugars consumption, in particular fructose, have reported AGEs accumulation in different tissues in association with peripheral insulin resistance and lipid metabolism alterations. The in vitro observation that fructose is one of the most rapid and effective glycating agent when compared to other sugars has prompted the investigation of the in vivo fructose-induced glycation. In particular, the widespread employment of fructose as sweetener has been ascribed by many experimental and observational studies for the enhancement of lipogenesis and intracellular lipid deposition. Indeed, diet-derived AGEs have been demonstrated to interfere with many cell functions such as lipid synthesis, inflammation, antioxidant defences, and mitochondrial metabolism. Moreover, emerging evidences also in humans suggest that this impact of dietary AGEs on different signalling pathways can contribute to the onset of organ damage in liver, skeletal and cardiac muscle, and brain, affecting not only metabolic control, but global health. Indeed, the here reviewed most recent reports on the effects of high sugars consumption and diet-derived AGEs on human health suggest the need to limit the dietary sources of AGEs, including added sugars, to prevent the development of metabolic diseases and related comorbidities.