ID: hypothesis-h-var-08a4d5c07a
Hypothesis
Gut Microbiome Remodeling to Prevent Systemic NLRP3 Priming in Neurodegeneration
Gut Microbiome Remodeling to Prevent Systemic NLRP3 Priming in Neurodegeneration proposes that intestinal dysbiosis creates systemic NLRP3 inflammasome priming through bacterial lipopolysaccharide (LPS) translocation, followed by seconda.
EvidencePending (0%)📖 51 cit🗣 1 debates✓ 26 support✗ 11 oppose
✓ All Quality Gates Passed
🧪 Overview
Mechanistic Overview
Gut Microbiome Remodeling to Prevent Systemic NLRP3 Priming in Neurodegeneration proposes that intestinal dysbiosis creates systemic NLRP3 inflammasome priming through bacterial lipopolysaccharide (LPS) translocation, followed by secondary activation triggers in the central nervous system. Circulating LPS binds to Toll-like receptor 4 (TLR4) on peripheral monocytes and brain-resident microglia, initiating NF-κB-mediated transcriptional upregulation of NLRP3, pro-IL-1β, and pro-caspase-1 without full inflammasome assembly. This priming state sensitizes cells to subsequent danger-associated molecular patterns (DAMPs) such as aggregated amyloid-β or extracellular ATP, which serve as signal 2 activators that promote NLRP3-PYCARD oligomerization, caspase-1 activation, and mature IL-1β secretion. The resulting chronic neuroinflammatory cascade perpetuates microglial activation, blood-brain barrier dysfunction, and progressive neurodegeneration through sustained cytokine production and oxidative stress.
Molecular and Cellular Rationale
...
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
graph TD
A["Intestinal Dysbiosis<br/>Pathogenic bacterial<br/>overgrowth"] --> B["Increased Intestinal<br/>Permeability<br/>Leaky gut syndrome"]
B --> C["LPS Translocation<br/>Bacterial endotoxin<br/>enters circulation"]
C --> D["TLR4 Activation<br/>Pattern recognition<br/>on immune cells"]
D --> E["NF-kappaB Signaling<br/>Transcriptional<br/>activation pathway"]
E --> F["NLRP3 Priming<br/>Upregulation of<br/>inflammasome components"]
E --> G["Pro-IL1B Expression<br/>Inactive cytokine<br/>precursor synthesis"]
E --> H["Pro-CASP1 Expression<br/>Inactive caspase-1<br/>precursor synthesis"]
C --> I["Microglial TLR4<br/>Brain-resident immune<br/>cell activation"]
I --> J["CNS NLRP3 Priming<br/>Neuroinflammatory<br/>sensitization"]
K["Neuronal DAMPs<br/>Amyloid-beta aggregates<br/>ATP release"] --> L["NLRP3-PYCARD<br/>Oligomerization<br/>Signal 2 activation"]
F --> L
J --> L
L --> M["Active CASP1<br/>Caspase-1 cleavage<br/>and activation"]
H --> M
M --> N["Mature IL1B<br/>Pro-inflammatory<br/>cytokine secretion"]
G --> N
N --> O["Sustained Neuroinflammation<br/>Chronic microglial<br/>activation state"]
O --> P["Blood-Brain Barrier<br/>Dysfunction<br/>Vascular permeability"]
O --> Q["Oxidative Stress<br/>ROS production<br/>cellular damage"]
P --> R["Progressive<br/>Neurodegeneration<br/>Cognitive decline"]
Q --> R
S["Microbiome Remodeling<br/>Therapeutic intervention<br/>probiotic treatment"] --> T["Restored Gut Barrier<br/>Reduced intestinal<br/>permeability"]
T --> U["Reduced LPS<br/>Translocation<br/>Decreased endotoxemia"]
U --> V["Prevented NLRP3<br/>Priming<br/>Neuroprotective effect"]
classDef normal fill:#4fc3f7,stroke:#2196f3,color:#0d0d1a
classDef therapeutic fill:#81c784,stroke:#4caf50,color:#0d0d1a
classDef pathology fill:#ef5350,stroke:#f44336,color:#0d0d1a
classDef outcome fill:#ffd54f,stroke:#ff9800,color:#0d0d1a
classDef molecular fill:#ce93d8,stroke:#9c27b0,color:#0d0d1a
class A,B,C pathology
class D,E,F,G,H,I,J,K,L,M,N molecular
class O,P,Q normal
class R outcome
class S,T,U,V therapeutic⚖️ Evidence
⚖️ Evidence Matrix26 supports11 contradicts
Supports
Gut microbiota-derived metabolites activate NLRP3 inflammasome in microglia, promoting neuroinflammation in AD mouse models.
Abstract
UK Biobank is a major prospective epidemiological study, including multimodal brain imaging, genetics and ongoing health outcomes. Previously, we published genome-wide associations of 3,144 brain imaging-derived phenotypes, with a discovery sample of 8,428 individuals. Here we present a new open resource of genome-wide association study summary statistics, using the 2020 data release, almost tripling the discovery sample size. We now include the X chromosome and new classes of imaging-derived phenotypes (subcortical volumes and tissue contrast). Previously, we found 148 replicated clusters of associations between genetic variants and imaging phenotypes; in this study, we found 692, including 12 on the X chromosome. We describe some of the newly found associations, focusing on the X chromosome and autosomal associations involving the new classes of imaging-derived phenotypes. Our novel associations implicate, for example, pathways involved in the rare X-linked STAR (syndactyly, telecant
Supports
Periodontal pathogen P. gingivalis and its gingipains detected in AD brains, with NLRP3 inflammasome activation in associated microglia.
Abstract
The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by NFE2L2) and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (KEAP1), are critical in the maintenance of redox, metabolic and protein homeostasis, as well as the regulation of inflammation. Thus, NRF2 activation provides cytoprotection against numerous pathologies including chronic diseases of the lung and liver; autoimmune, neurodegenerative and metabolic disorders; and cancer initiation. One NRF2 activator has received clinical approval and several electrophilic modifiers of the cysteine-based sensor KEAP1 and inhibitors of its interaction with NRF2 are now in clinical development. However, challenges regarding target specificity, pharmacodynamic properties, efficacy and safety remain.
Supports
NLRP3 inflammasome activation in microglia drives tau hyperphosphorylation and aggregation via ASC speck seeding.
Abstract
Alzheimer's disease is characterized by the accumulation of amyloid-beta in plaques, aggregation of hyperphosphorylated tau in neurofibrillary tangles and neuroinflammation, together resulting in neurodegeneration and cognitive decline1. The NLRP3 inflammasome assembles inside of microglia on activation, leading to increased cleavage and activity of caspase-1 and downstream interleukin-1β release2. Although the NLRP3 inflammasome has been shown to be essential for the development and progression of amyloid-beta pathology in mice3, the precise effect on tau pathology remains unknown. Here we show that loss of NLRP3 inflammasome function reduced tau hyperphosphorylation and aggregation by regulating tau kinases and phosphatases. Tau activated the NLRP3 inflammasome and intracerebral injection of fibrillar amyloid-beta-containing brain homogenates induced tau pathology in an NLRP3-dependent manner. These data identify an important role of microglia and NLRP3 inflammasome activation in the
Supports
Bacterial amyloids from gut microbiota cross-seed Aβ aggregation and prime NLRP3 inflammasome in TLR2-dependent manner.
Abstract
Kawasaki disease (KD) has become the most common cause of acquired heart disease in children and is also a risk factor for ischemic heart disease in adults. However, Kawasaki disease lacks specific laboratory diagnostic indices. Thus, this study analyzed the T cell activation profiles of Kawasaki disease and assessed their value in the diagnosis of Kawasaki disease and the prediction of intravenous immunoglobulin (IVIG) sensitivity. We analyzed human leukocyte antigen-DR (HLA-DR), CD69 and CD25 expression on peripheral blood CD4+ and CD8+ T cells during the acute phase of KD. We compared the percentages of HLA-DR+/CD69+/CD25+ T cells in the CD4+ and CD8+ T cell populations of IVIG-effective and IVIG-resistant groups. Receiver operating characteristic curves were used to assess the diagnostic value of the above parameters. The median percentage of CD8+HLA-DR+ T cells and the median ratio of CD8+HLA-DR+ T cells/CD8+CD25+ T cells were significantly elevated in the patient group compared w
Supports
Fecal microbiota transplant from AD patients to germ-free mice induces neuroinflammation and NLRP3-dependent cognitive impairment.
Abstract
OBJECTIVE: To analyze the fluorine-18 fludeoxyglucose PET/computed tomography (18F-FDG PET/CT) findings of retroperitoneal leiomyosarcoma (RLMS) and the role of this method in differentiating between benign and malignant masses and classifying the malignant degree to improve the understanding of this rare disease. METHODS: Eight leiomyomas (A group), 13 RLMSs (B group), and 20 postoperative recurrence/metastasis RLMSs (C group) were enrolled. PET/CT features of B group were analyzed. The differences of metabolic parameters between three groups were compared, receiver operating characteristic (ROC) curve analysis was performed to group A and B, and correlation analysis was performed to subgroup B. RESULTS: (1) The RLMS patients were more likely to be female, and PET/CT showed a high degree of heterogeneous metabolism in the soft tissue mass. (2) The standardized uptake value (SUV) of RLMS were significantly higher than those of benign leiomyomas (P < 0.05). The area under the ROC curve
Supports
Gut-derived short-chain fatty acids regulate microglial inflammasome priming; dysbiosis reduces protective butyrate levels.
Abstract
In the interest of the trend towards miniaturization of electronic gadgets, this study demonstrates a high-density data storage device with a very simple three-stacking layer consisting of only one charge trapping layer. A simple solution-processed technique has been used to fabricate the tristable non-volatile memory. The three-stacking layer was constructed in between two metals to form a two-terminal metal-insulator-metal structure. The fabricated device showed a large multilevel memory hysteresis window with a measured ON/OFF current ratio of 107 that might be attributed to the high charge trapped in molybdenum disulphide (MoS2) flakes-graphene quantum dots (GQDs) heterostructure. Transmission electron microscopy was performed to examine the orientation of MoS2-GQD and mixture dispersion preparation method. The obtained electrical data was used further to speculate the possible transport mechanisms through the fabricated device by a curve fitting technique. Also, endurance cycle an
Supports
MCC950, a selective NLRP3 inhibitor, reduces Aβ accumulation and rescues cognitive function in APP/PS1 mice.
Abstract
In this study we characterise three tandem promoters (PR1-1, PR1-2 and PR1-3) within the PR1 regulatory region of the Escherichia coli kps capsule gene cluster. Transcription from promoter PR1-2 was dependent on the activity of the upstream promoter PR1-1, which activated PR1-2 via transcription coupled DNA supercoiling. During growth at 37 °C a temporal pattern of transcription from all three promoters was observed with maximum transcriptional activity evident during mid-exponential phase followed by a sharp decrease in activity as the cells enter stationary phase. The growth phase dependent transcription was regulated by Integration Host Factor (IHF), which bound within the PR1 region to repress transcription from PR1-2 and PR1-3. This pattern of transcription was mirrored by growth phase dependent expression of the K1 capsule. Overall these data reveal a complex pattern of transcriptional regulation for an important virulence factor with IHF playing a role in regulating growth phase
Supports
Oral antibiotic cocktail reduces microglial NLRP3 activation and amyloid plaque burden in 5xFAD mice via gut-brain axis modulation.
Abstract
BACKGROUND: Hands are the most common vehicle for the transmission of pathogens within the healthcare environment. Hand hygiene is the leading measure for reducing healthcare-associated infections (HCAIs) and preventing the spread of antimicrobial resistance. OBJECTIVE: An interventional study was carried out to evaluate the knowledge, attitude and practices of hand hygiene among third semester medical students. MATERIALS AND METHODS: A total of 152 medical students were evaluated using a pretest self-structured questionnaire to assess the knowledge, attitude and practices regarding hand hygiene. The students were trained by faculty of microbiology vigorously with the help of a lecture and demonstration on hand hygiene followed by hands-on training. The same group of students were then distributed the post-training questionnaire. The pre-training and post training data was analyzed and compared. RESULT: There was a significant improvement in knowledge, attitude and practice towards han
Supports
Helicobacter pylori infection associated with increased AD risk in meta-analysis of 11 studies; eradication reduces cognitive decline trajectory.
Abstract
This studystudy focuses on the effect of radiation treatment and hydrogen peroxide (H2O2) on the toxicity of anticancer methotrexate. For cytotoxicity, different bioassays such as Allium cepa, hemolytic, brine shrimp were employed. The Ames test was used for mutagenicity analysis. The solutions having concentrations 5, 10 and 15 ppm were irradiated with UV radiation exposure time 15, 30, 45, 60, 75 and 90 min and gamma radiation absorbed doses 0.3, 0.6, 0.9, 1.2, 2, 3 and 4 kGy in combination with with H2O2. There was a clear difference observed for aqueous solution before and after treatment with reference to cytotoxicity and mutagenicity. In Allium cepa test, a 47.07, 44.36 and 38.23% increase in root length (RL), root count (RC) and mitotic index (MI) was observed, respectively, for UV/H2O2 treatment and in the case of gamma/H2O2 treatment, the RL, RC and MI were increased up to 49.39, 52.63 and 52.38%, respectively. Brine shrimp test has shown 85.95 and 91.30% decrease in toxicity
Supports
Caspase-1 (CASP1) cleaves IL-1β and IL-18 downstream of NLRP3; genetic deletion of CASP1 is neuroprotective in tau transgenic mice.
Abstract
Sodium-glucose cotransporter-2 (SGLT2) is selectively expressed in the human kidney, where it executes reabsorption of filtered glucose with a high capacity; it may be overactive in patients with diabetes, especially in the early, hyperfiltering stage of the disease. As a therapeutic target, SGLT2 has been successfully engaged by orally active, selective agents. Initially developed as antihyperglycemic drugs, SGLT2 inhibitors have deployed a range of in vivo actions. Consequences of their primary effect, i.e., profuse glycosuria and natriuresis, involve hemodynamic (plasma volume and blood pressure reduction) and metabolic pathways (increase in lipid oxidation and ketogenesis at the expense of carbohydrate utilization); the hormonal mediation extends to insulin, glucagon, and gastrointestinal peptides. Their initial trial in high-risk patients with diabetes has provided evidence for marked reduction of cardiovascular risk. This review focuses on the quantitative pharmacology of SGLT2 i
Supports
Trained immunity of microglia by peripheral infection leads to sustained NLRP3 inflammasome priming and accelerated neurodegeneration months after infection resolution.
Abstract
Innate immune memory is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished-training and tolerance. These are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages (microglia) that persists for at least six months. Strikingly, in a mouse model of Alzheimer's pathology, immune training exacerbates cerebral β-amyloidosis and immune tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an i
Supports
Elevated expression of the NLRP3 inflammasome in post-mortem brain white matter and immune cells in multiple sclerosis.
Abstract
BACKGROUND: The nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is a signalling hub associated with the pathogenesis of neuroinflammatory conditions such as multiple sclerosis (MS). NLRP3 inflammasome activation requires interplay between pathogen-/damage-associated molecular patterns and other soluble factors, which initiates inflammation to promote the secretion of the cytokine, interleukin (IL)-1β. OBJECTIVE: To determine if the expression of NLRP3 inflammasome signalling components is altered in the brain and in immune cells in MS. METHODS: Using post-mortem brain tissue from 21 cases, including 8 non-MS control, 7 primary progressive (PP) MS and 6 secondary progressive (SP) MS cases, alongside peripheral blood mononuclear cells (PBMCs) isolated from 45 subjects including healthy controls (n = 23), and people with (pw) a relapsing remitting (RR) (n = 15), SP (n = 5) or PP (n = 2) form of MS, we profiled the expression of
Supports
NLRP3 Inflammasome and Polycystic Ovary Syndrome (PCOS): A Novel Profile in Adipose Tissue.
Abstract
Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by chronic low-grade inflammation. The NLRP3 inflammasome has been implicated in various inflammatory conditions, but its role in PCOS remains unclear. This study aimed to investigate whether the NLRP3 inflammasome and its associated components, IL-1β, CASP-1, and PYCARD, are involved in the pathogenesis of PCOS. Gene and protein expression levels of NLRP3, IL-1β, CASP-1, and PYCARD were assessed in adipose tissue samples (visceral and subcutaneous) from women with and without PCOS using qPCR and Western blotting. Contrary to our initial hypothesis, CASP-1 gene expression was significantly higher in non-PCOS participants across all adipose depots examined. Similarly, NLRP3 protein levels were significantly upregulated in visceral adipose tissue (VAT) and in combined adipose samples from the non-PCOS group. No significant group differences were observed in the gene expression of NLRP3, IL-1β, or PYCARD. These
Supports
Δ(9)-Tetrahydrocannabinol and cannabidiol selectively suppress toll-like receptor (TLR) 7- and TLR8-mediated interleukin-1β production by human CD16(+) monocytes by inhibiting its post-translational maturation.
Abstract
Monocytes are innate immune cells that release inflammatory factors upon detection of infectious and injurious stimuli. CD16+ monocytes, a subset of the total monocyte population, are associated with acute and chronic inflammation in human immunodeficiency virus-associated neurocognitive disorder and rheumatoid arthritis. Given the role monocytes play in regulating the host immune response, this investigation explored the effects of cannabinoids on the monocyte secretome for potential therapeutic applications. Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are major cannabis-derived compounds established to have immune-modulating properties. Despite a rise in medical cannabis use, the specific mechanism by which THC and CBD modulate the inflammatory response, including by human monocytes remains poorly understood. We hypothesized that THC and CBD suppress toll-like receptor (TLR) 7- or TLR8-induced inflammatory profiles by CD16+ and CD16- monocytes, specifically interleukin (IL) 1
Supports
Nlrc4 Inflammasome Expression After Acute Myocardial Infarction in Rats.
Abstract
Acute myocardial necrosis activates the immune response and inflammatory processes. Although the initial response is helpful in restoring tissue injury, dysregulated and exacerbated inflammation contributes to the progression of cardiac remodeling. Inflammasomes play important roles in post-infarction inflammation. NALP1/NLRP1, NLRP 3, and NLRC4 are the best-known inflammasomes. NLRP3, which has received the most study in cardiovascular disease, has been linked to increased IL-1β (IL1B) production and caspase-1 activity, as well as impaired cardiac function. The role of NLRP1 and NLRC4 inflammasomes after acute myocardial infarction (MI) is poorly understood. We evaluated the expression of myocardial inflammasomes and inflammatory markers 72 h after MI in rats. Male Wistar rats were divided into Sham (n = 15) and MI (n = 16) groups. MI was induced by ligating the left anterior descending coronary artery. Infarct size was assessed by histology. Myocardial protein and gene expression was
Supports
USP5 attenuates NLRP3 inflammasome activation by promoting autophagic degradation of NLRP3
Supports
USP22 suppresses the NLRP3 inflammasome by degrading NLRP3 via ATG5-dependent autophagy
Supports
Small molecule-driven NLRP3 inflammation inhibition via interplay between ubiquitination and autophagy: implications for Parkinson disease
Supports
The macrophage-specific V-ATPase subunit ATP6V0D2 restricts inflammasome activation and bacterial infection by facilitating autophagosome-lysosome fusion
Supports
Andrographolide Attenuates NLRP3 Inflammasome Activation and Airway Inflammation in Exacerbation of Chronic Obstructive Pulmonary Disease
Supports
Berberine Protects Against NLRP3 Inflammasome via Ameliorating Autophagic Impairment in MPTP-Induced Parkinson's Disease Model.
Supports
Inflammasome and toll-like receptor signaling in human monocytes after successful cardiopulmonary resuscitation.
Supports
Small molecule-driven mitophagy-mediated NLRP3 inflammasome inhibition is responsible for the prevention of colitis-associated cancer.
Supports
SCFA-producing bacteria depletion is associated with elevated serum LPS and IL-1β levels in early-stage Alzheimer's patients.
Supports
Restoration of SCFA production by Akkermansia and Faecalibacterium species strengthens intestinal barrier function, reducing bacterial LPS translocation into systemic circulation.
Supports
NLRP3 inflammasome activation in microglia drives blood-brain barrier dysfunction and progressive neurodegeneration through sustained cytokine production and oxidative stress.
Contradicts
NLRP3 inflammasome also serves protective antimicrobial functions in the CNS; complete inhibition may increase infection susceptibility.
Contradicts
Blood-brain barrier limits microbial products from reaching CNS; gut-brain inflammasome priming may be an indirect rather than direct mechanism.
Abstract
In the interest of the trend towards miniaturization of electronic gadgets, this study demonstrates a high-density data storage device with a very simple three-stacking layer consisting of only one charge trapping layer. A simple solution-processed technique has been used to fabricate the tristable non-volatile memory. The three-stacking layer was constructed in between two metals to form a two-terminal metal-insulator-metal structure. The fabricated device showed a large multilevel memory hysteresis window with a measured ON/OFF current ratio of 107 that might be attributed to the high charge trapped in molybdenum disulphide (MoS2) flakes-graphene quantum dots (GQDs) heterostructure. Transmission electron microscopy was performed to examine the orientation of MoS2-GQD and mixture dispersion preparation method. The obtained electrical data was used further to speculate the possible transport mechanisms through the fabricated device by a curve fitting technique. Also, endurance cycle an
Contradicts
P. gingivalis detection in AD brains may reflect post-mortem artifact rather than causal pathology.
Abstract
Optical-coherence-tomography (OCT) is a non-destructive tool for biofilm imaging, not requiring staining, and used to measure biofilm thickness and putative comparison of biofilm structure based on signal intensity distributions in OCT-images. Quantitative comparison of biofilm signal intensities in OCT-images, is difficult due to the auto-scaling applied in OCT-instruments to ensure optimal quality of individual images. Here, we developed a method to eliminate the influence of auto-scaling in order to allow quantitative comparison of biofilm densities in different images. Auto- and re-scaled signal intensities could be qualitatively interpreted in line with biofilm characteristics for single and multi-species biofilms of different strains and species (cocci and rod-shaped organisms), demonstrating qualitative validity of auto- and re-scaling analyses. However, specific features of pseudomonas and oral multi-species biofilms were more prominently expressed after re-scaling. Quantitativ
Contradicts
Microbiome composition is highly variable between individuals; identifying universal therapeutic targets for prevention is challenging.
Abstract
COVID-19 vaccination programmes are ongoing worldwide. Neutralizing antibodies are thought to be key for host protection against COVID-19; however, strategies that focus only on neutralizing antibodies may not be sufficient to cope with the pandemic in the longer term owing to the decay of antibody titres and the emergence of antibody-escape variants of SARS-CoV-2. Here, we describe the protective roles of T cells in COVID-19 and the conservation of T cell epitopes in SARS-CoV-2 variants of concern, and discuss the potential contribution of T cell-oriented strategies to controlling the COVID-19 pandemic. This Comment article proposes that T cell-oriented vaccine strategies should be considered to control the COVID-19 pandemic in the longer term, given declining levels of neutralizing antibodies with time after vaccination or infection and the emergence of viral escape variants.
Contradicts
Long-term NLRP3 inhibition may impair peripheral innate immune surveillance and increase cancer risk.
Abstract
BACKGROUND AND OBJECTIVES: Patients who have failed a transplant are at increased risk of repeat transplant failure. We determined access to transplantation and transplant outcomes in patients with and without a history of transplant failure. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this observational study of national data, the proportion of waitlisted patients and deceased donor transplant recipients with transplant failure was determined before and after the new kidney allocation system. Among patients initiating maintenance dialysis between May 1995 and December 2014, the likelihood of deceased donor transplantation was determined in patients with (n=27,459) and without (n=1,426,677) a history of transplant failure. Among transplant recipients, allograft survival, the duration of additional kidney replacement therapy required within 10 years of transplantation, and the association of transplantation versus dialysis with mortality was determined in patients with and without
Contradicts
Triptolide prevents LPS-induced skeletal muscle atrophy via inhibiting NF-κB/TNF-α and regulating protein synthesis/degradation pathway
Abstract
BACKGROUND AND PURPOSE: Increasing evidence suggests systemic inflammation-caused skeletal muscle atrophy as a major clinical feature of cachexia. Triptolide obtained from Tripterygium wilfordii Hook F possesses potent anti-inflammatory and immunosuppressive effects. The present study aims to evaluate the protective effects and molecular mechanisms of triptolide on inflammation-induced skeletal muscle atrophy. EXPERIMENTAL APPROACH: The effects of triptolide on skeletal muscle atrophy were investigated in LPS-treated C2C12 myotubes and C57BL/6 mice. Protein expressions and mRNA levels were analysed by western blot and qPCR, respectively. Skeletal muscle mass, volume and strength were measured by histological analysis, micro-CT and grip strength, respectively. Locomotor activity was measured using the open field test. KEY RESULTS: Triptolide (10-100 fM) up-regulated protein synthesis signals (IGF-1/p-IGF-1R/IRS-1/p-Akt/p-mTOR) and down-regulated protein degradation signal atrogin-1 in C2C12 myotubes. In LPS (100 ng·ml-1 )-treated C2C12 myotubes, triptolide up-regulated MyHC, IGF-1, p-IGF-1R, IRS-1 and p-Akt. Triptolide also down-regulated ubiquitin-proteasome molecules (n-FoxO3a/atrogin-1/MuRF1), proteasome activity, autophagy-lysosomal molecules (LC3-II/LC3-I and Bnip3) and inflammatory mediators (NF-κB, Cox-2, NLRP3, IL-1β and TNF-α). However, AG1024, an IGF-1R inhibitor, suppressed triptolide-mediated effects on MyHC, myotube diameter, MuRF1 and p62 in LPS-treated C2C12 myo
Contradicts
Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice
Abstract
Parkinson's disease (PD) is characterized by a profound loss of dopaminergic neurons in the substantia nigra, accompanied by chronic neuroinflammation, mitochondrial dysfunction, and widespread accumulation of α-synuclein-rich protein aggregates in the form of Lewy bodies. However, the mechanisms linking α-synuclein pathology and dopaminergic neuronal death to chronic microglial neuroinflammation have not been completely elucidated. We show that activation of the microglial NLR family pyrin domain containing 3 (NLRP3) inflammasome is a common pathway triggered by both fibrillar α-synuclein and dopaminergic degeneration in the absence of α-synuclein aggregates. Cleaved caspase-1 and the inflammasome adaptor protein apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) were elevated in the substantia nigra of the brains of patients with PD and in multiple preclinical PD models. NLRP3 activation by fibrillar α-synuclein in mouse microglia resulted in a delayed but robust activation of the NLRP3 inflammasome leading to extracellular interleukin-1β and ASC release in the absence of pyroptosis. Nanomolar doses of a small-molecule NLRP3 inhibitor, MCC950, abolished fibrillar α-synuclein-mediated inflammasome activation in mouse microglial cells and extracellular ASC release. Furthermore, oral administration of MCC950 in multiple rodent PD models inhibited inflammasome activation and effectively mitigated motor deficits, nigrostriatal dopami
Contradicts
GSK872 and necrostatin-1 protect retinal ganglion cells against necroptosis through inhibition of RIP1/RIP3/MLKL pathway in glutamate-induced retinal excitotoxic model of glaucoma
Abstract
BACKGROUND: Glaucoma, the major cause of irreversible blindness worldwide, is characterized by progressive degeneration of retinal ganglion cells (RGCs). Current treatments for glaucoma only slow or partially prevent the disease progression, failing to prevent RGCs death and visual field defects completely. Glutamate excitotoxicity via N-methyl-D-aspartic acid (NMDA) receptors plays a vital role in RGCs death in glaucoma, which is often accompanied by oxidative stress and NLRP3 inflammasome activation. However, the exact mechanisms remain unclear. METHODS: The glutamate-induced R28 cell excitotoxicity model and NMDA-induced mouse glaucoma model were established in this study. Cell counting kit-8, Hoechst 33342/PI dual staining and lactate dehydrogenase release assay were performed to evaluate cell viability. Annexin V-FITC/PI double staining was used to detect apoptosis and necrosis rate. Reactive oxygen species (ROS) and glutathione (GSH) were used to detect oxidative stress in R28 cells. Levels of proinflammatory cytokines were measured by qRT-PCR. Transmission electron microscopy (TEM) was used to detect necroptotic morphological changes in RGCs. Retinal RGCs numbers were detected by immunofluorescence. Hematoxylin and eosin staining was used to detect retinal morphological changes. The expression levels of RIP1, RIP3, MLKL and NLRP3 inflammasome-related proteins were measured by immunofluorescence and western blotting. RESULTS: We found that glutamate excitotoxicity induc
Contradicts
The NLRP3-inflammasome inhibitor MCC950 improves cardiac function in a HFpEF mouse model
Abstract
Heart failure with preserved ejection fraction (HFpEF) is posing a significant medical challenge due to its growing prevalence, high hospitalization rates and limited response to current treatment options. Accumulating evidence suggests that a comorbidity-driven systemic pro-inflammatory state, including activation of the NLRP3 inflammasome, contributes to the pathogenesis of HFpEF. This study aimed to investigate the potential cardiac protective effects of the selective NLRP3 inhibitor MCC950, in a mouse model of HFpEF. HFpEF was obtained in 18-22 months old female mice using high-fat diet (HFD) and angiotensin II (AngII) infusion. Mice developed HFpEF and comorbidities such as obesity, type 2 diabetes, and hypertension. MCC950 was added to HFD and groups were treated for four weeks until the study endpoint. MCC950 treatment resulted in lower plasma IL-18 levels (-47.3 %), illustrating target engagement. First, we observed that MCC950 treatment improved left ventricular function, demonstrated by enhanced global longitudinal strain (GLS, 3.9 %, P<0.01) and reverse peak longitudinal strain (RPLSR, +46.8 %, P<0.05). Second, MCC950 reduced cardiac hypertrophy (cardiomyocyte size -19.5 %, P<0.001) and fibrosis (-32.5 %, P<0.05), accompanied by lower expression of pro-fibrotic genes. Finally, MCC950 treatment reduced macrophage infiltration in left ventricular tissue and attenuated macrophage accumulation in visceral adipose tissue, even more as compared to caloric restriction. Ov
Contradicts
Sepsis and the Liver
Abstract
BACKGROUND/OBJECTIVES: Sepsis-associated liver injury (SALI) is a critical and often early complication of sepsis, defined by distinct hyper-inflammatory and immunosuppressive phases that shape patient phenotypes. METHODS: Characterizing these phases establishes a foundation for immunomodulation strategies tailored to individual immune responses, as discussed subsequently. RESULTS: The initial inflammatory response activates pathways such as NF-κB and the NLRP3 inflammasome, leading to a cytokine storm that damages hepatocytes and is frequently associated with higher SOFA scores and a higher risk of 28-day mortality. Kupffer cells and infiltrating neutrophils exacerbate hepatic injury by releasing proinflammatory cytokines and reactive oxygen species, thereby causing cellular damage and prolonging ICU stays. During the subsequent immunosuppressive phase, impaired infection control and tissue repair can result in recurrent hospital-acquired infections and a poorer prognosis. Concurrently, hepatocytes undergo significant metabolic disturbances, notably impaired fatty acid oxidation due to downregulation of transcription factors such as PPARα and HNF4α. This metabolic alteration corresponds with worsening liver function tests, which may reflect the severity of liver failure in clinical practice. Mitochondrial dysfunction, driven by oxidative stress and defective autophagic quality control, impairs cellular energy production and induces hepatocyte death, which is closely linked t
Contradicts
Bone marrow vacuolization to curative strategies: Evolving paradigms in VEXAS syndrome management
Abstract
VEXAS syndrome (vacuoles, E1 enzyme, X-linked alongside autoinflammatory and somatic) is a severe aggressive inflammation disorder arising in adults that results from acquired changes to the UBA1 gene. These genetic alterations lead to widespread chronic systemic inflammation, prominent features of clonal hematopoiesis, and worsening cytopenic decays alongside hematological malignancies. The grim prognosis includes survival-seeking patients facing life-threatening infections, bone marrow failure or thrombotic complications with only 76 % three-year survival rate. It mainly occurs in older men but rare cases in women stem from atypical patterns of X-chromosome inactivation. This syndrome shares characteristics with autoimmune disorders like relapsing polychondritis and blood disorders predominantly myelodysplastic syndromes. Diagnosis requires UBA1 genetic analysis and bone marrow examination which shows characteristic vacuolization in myeloid and erythroid progenitors. Current therapeutic approaches concentrate on fighting inflammation alongside supportive therapy. This includes infection control, transfusion administration, hypomethylating agents such as azacitidine, which provide the dual benefit of reducing mutant clones alongside inflammation, as well as immunosuppressive drugs, steroids, and Janus Kinase (JAK) inhibitors. Even though allogeneic hematopoietic stem cell transplantation (HSCT) remains the sole option for a cure, its extensive toxicity limits widespread appl
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — NLRP3
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for NLRP3, CASP1, IL1B, PYCARD from GTEx v10.
💉 Clinical Trials (3)Relevance: 4%
0
Active
Active
0
Completed
Completed
0
Total Enrolled
Total Enrolled
Clinical trial NCT03808389Unknown
Unknown·NCT03808389
Clinical trial NCT03671785Unknown
Unknown·NCT03671785
Clinical trial NCT02269150Unknown
Unknown·NCT02269150
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for NLRP3, CASP1, IL1B, PYCARD.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
💰 Estimated Development
Cost
$0
Timeline
18 months
🏆 Tournament
🏆 Arenas / Elo
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📊 Market Indicators
7d Trend
↘
Falling
7d Momentum
▼ 3.7%
Volatility
Low
0.0122
Events (7d)
4
Price History
▼24.7%💾 Resource Usage
LLM Tokens
40,932
$0.2456
Total Cost
$0.2456
📖 References (9)
- NLRP3 inflammasome activation drives tau pathology.["Ising C" et al.. Nature (2019)
- An expanded set of genome-wide association studies of brain imaging phenotypes in UK Biobank.["Smith S" et al.. Nature neuroscience (2021)
- Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases.["Cuadrado A" et al.. Nature reviews. Drug discovery (2019)
- Intravenous immunoglobulin treatment responsiveness depends on the degree of CD8+ T cell activation in Kawasaki disease.["Ye Q" et al.. Clinical immunology (Orlando, Fla.) (2016)
- Potential application value of PET/computed tomography in retroperitoneal leiomyosarcoma and a literature review.["Gao Y" et al.. Nuclear medicine communications (2021)
- Electrical transportation mechanisms of molybdenum disulfide flakes-graphene quantum dots heterostructure embedded in polyvinylidene fluoride polymer.["Ooi P" et al.. Scientific reports (2019)
- Bacterial Density and Biofilm Structure Determined by Optical Coherence Tomography.["Hou J" et al.. Scientific reports (2019)
- T cell-oriented strategies for controlling the COVID-19 pandemic.["Noh J" et al.. Nature reviews. Immunology (2021)
- Access to Kidney Transplantation after a Failed First Kidney Transplant and Associations with Patient and Allograft Survival: An Analysis of National Data to Inform Allocation Policy.["Clark S" et al.. Clinical journal of the American Society of Nephrology : CJASN (2019)
Parent Context
▸Metadata
| _origin | {'url': None, 'type': 'internal', 'tracked_at': '2026-04-27T16:04:41.875944'} |
| description | ## Mechanistic Overview Gut Microbiome Remodeling to Prevent Systemic NLRP3 Priming in Neurodegeneration starts from the claim that modulating NLRP3, CASP1, IL1B, PYCARD within the disease context of |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
10%
Debates
0
Incoming
2
Outgoing
2
0 supporting
0 contradicting
0 neutral
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