Mechanistic 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 neurodegeneration can redirect a disease-relevant process. The original description reads: “## 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 neurodegeneration can redirect a disease-relevant process. The original description reads: “## Molecular Mechanism and Rationale The core molecular mechanism involves a two-step process where 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 components 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. ## Preclinical Evidence Multiple animal studies demonstrate that germ-free mice or antibiotic-treated rodents show reduced NLRP3 inflammasome activation and attenuated neuroinflammation compared to conventionally housed controls, with restoration of pathology upon recolonization with dysbiotic microbiomes. Genetic evidence from NLRP3 knockout mice reveals protection against LPS-induced cognitive decline and reduced tau phosphorylation, while IL-1β neutralization prevents gut permeability-associated neurodegeneration in multiple AD models. Cell culture studies using primary microglia demonstrate that pre-exposure to physiologically relevant LPS concentrations (10-100 ng/mL) dramatically amplifies subsequent amyloid-β-induced IL-1β secretion compared to naive cells, confirming the priming hypothesis. Human microbiome studies show consistent depletion of SCFA-producing Bifidobacterium and Faecalibacterium species alongside elevated serum LPS and IL-1β levels in early-stage Alzheimer’s patients compared to age-matched controls. ## Therapeutic Strategy The therapeutic approach centers on microbiome remodeling through targeted prebiotics, next-generation probiotics, and fecal microbiota transplantation to restore SCFA production and intestinal barrier function while reducing systemic LPS exposure. Specific interventions include encapsulated consortia of Akkermansia muciniphila, Faecalibacterium prausnitzii, and Bifidobacterium longum designed to survive gastric transit and establish stable colonization in the distal intestine. Complementary strategies involve NLRP3 small molecule inhibitors such as MCC950 or CY-09 for direct inflammasome blockade, potentially delivered via blood-brain barrier-penetrant nanoparticle formulations to achieve therapeutic CNS concentrations while minimizing systemic immunosuppression. Combination therapy pairing microbiome restoration with intermittent NLRP3 inhibition could provide synergistic neuroprotection by addressing both the upstream priming stimulus and downstream inflammatory cascade. ## Biomarkers and Endpoints Primary biomarkers include fecal microbiome analysis focusing on Firmicutes/Bacteroidetes ratios and SCFA metabolite profiling, alongside serum measurements of LPS-binding protein, soluble CD14, and IL-1β as indicators of bacterial translocation and inflammasome activation. Cerebrospinal fluid levels of IL-1β, NLRP3, and ASC (PYCARD) serve as direct CNS inflammation markers, while plasma neurofilament light chain and GFAP indicate neuronal damage and astroglial activation respectively. Clinical endpoints encompass cognitive assessment batteries (MMSE, ADAS-Cog), neuroimaging measures of hippocampal volume and white matter integrity, and functional connectivity patterns measured by resting-state fMRI to capture synaptic network changes preceding overt neurodegeneration. ## Potential Challenges The primary scientific risk involves the complexity of microbiome-brain interactions, where individual variations in baseline microbiota, genetics, and diet may influence therapeutic responses unpredictably, necessitating personalized intervention strategies. Blood-brain barrier penetration remains challenging for both probiotic organisms and synthetic NLRP3 inhibitors, potentially requiring novel delivery systems such as focused ultrasound or engineered bacterial vectors to achieve therapeutic CNS concentrations. Off-target effects of prolonged inflammasome inhibition could increase infection susceptibility or impair beneficial inflammatory responses required for tissue repair and pathogen clearance. ## Connection to Neurodegeneration This mechanism directly contributes to Alzheimer’s pathology by creating a chronic inflammatory environment that accelerates amyloid-β aggregation and tau hyperphosphorylation through IL-1β-mediated kinase activation, particularly glycogen synthase kinase-3β and cyclin-dependent kinase 5. The sustained microglial activation driven by systemic NLRP3 priming impairs amyloid clearance mechanisms while promoting synaptic pruning and dendritic spine loss through complement cascade activation and cytokine-mediated excitotoxicity. Additionally, chronic IL-1β signaling disrupts synaptic plasticity by interfering with long-term potentiation and promoting AMPA receptor internalization, directly linking gut-derived inflammation to cognitive decline and memory formation deficits characteristic of early Alzheimer’s disease.” Framed more explicitly, the hypothesis centers NLRP3, CASP1, IL1B, PYCARD within the broader disease setting of neurodegeneration. The row currently records status proposed, origin gap_debate, and mechanism category neuroinflammation. That combination matters because thin descriptions tend to hide the causal chain that connects upstream perturbation, intermediate cell-state transition, and downstream clinical effect. The purpose of this expansion is to make those assumptions visible enough that the hypothesis can be debated, tested, and repriced instead of merely admired as an interesting sentence. The decision-relevant question is whether modulating NLRP3, CASP1, IL1B, PYCARD or the surrounding pathway space around Gut-brain axis TLR4/NF-κB priming of NLRP3 inflammasome in microglia can redirect a disease process rather than merely decorate it with a biomarker change. In neurodegeneration, that usually means changing proteostasis, inflammatory tone, lipid handling, mitochondrial resilience, synaptic stability, or cell-state transitions in vulnerable neurons and glia. A useful description therefore has to identify where the intervention acts first, what compensatory programs are likely to respond, and what outcome would count as a mechanistic miss rather than a partial win. SciDEX scoring currently records confidence 0.69, mechanistic plausibility 0.80, and clinical relevance 0.04. ## Molecular and Cellular Rationale The nominated target genes are NLRP3, CASP1, IL1B, PYCARD and the pathway label is Gut-brain axis TLR4/NF-κB priming of NLRP3 inflammasome in microglia. Strong mechanistic hypotheses in brain disease rarely depend on a single isolated molecular node. Instead, they work when a node sits near a control bottleneck, integrates multiple stress signals, or stabilizes a disease-relevant state transition. That is the standard this hypothesis should be held to. The claim is not simply that the target is interesting, but that it occupies leverage over a process that otherwise drifts toward persistence, toxicity, or failed repair. Gene-expression context on the row adds an important constraint: Gene Expression Context NLRP3 (NLR Family Pyrin Domain Containing 3): - Innate immune sensor; forms inflammasome complex with ASC (PYCARD) and pro-caspase-1 - Allen Human Brain Atlas: primarily expressed in microglia; low in neurons and astrocytes - NLRP3 expression increases 3-5× in AD microglia surrounding amyloid plaques - Activated by Aβ fibrils, tau aggregates, ROS, and extracellular ATP - NLRP3 knockout mice crossed with APP/PS1 show 50% reduced plaque burden and preserved cognition - MCC950 (NLRP3 inhibitor) rescues spatial memory in AD mouse models CASP1 (Caspase-1): - Inflammatory caspase; effector protease of the inflammasome - Cleaves pro-IL-1β and pro-IL-18 into mature inflammatory cytokines - Allen Human Brain Atlas: expressed in microglia and monocyte-derived macrophages in brain - Active caspase-1 detected in AD hippocampus by immunohistochemistry; correlates with CDR score - Also cleaves gasdermin D (GSDMD) to form membrane pores → pyroptotic cell death - VX-765 (caspase-1 inhibitor) reduces Aβ burden and inflammation in J20 mice IL1B (Interleukin-1β): - Pro-inflammatory cytokine; central mediator of neuroinflammation in AD - Allen Human Brain Atlas: induced expression in microglia; minimal constitutive expression - IL-1β elevated 2-6× in AD brain, CSF, and plasma - Drives tau phosphorylation via p38-MAPK and activates astrocytic A1 neurotoxic phenotype - Chronic IL-1β exposure impairs hippocampal LTP and reduces BDNF expression - Anti-IL-1β therapy (canakinumab) reduced dementia incidence in CANTOS cardiovascular trial PYCARD (ASC / Apoptosis-Associated Speck-like Protein): - Adaptor protein; bridges NLRP3 sensor to caspase-1 effector via CARD-CARD interaction - ASC specks released from pyroptotic microglia propagate inflammation to neighboring cells - ASC specks cross-seed Aβ aggregation — direct molecular link between inflammation and amyloidosis - Extracellular ASC detectable in AD CSF; proposed as inflammatory biomarker Microbial Inflammasome Priming: - Gut microbiome-derived molecules (LPS, short-chain fatty acids) prime NLRP3 via NF-κB signal 1 - Dysbiosis in AD patients increases circulating LPS, lowering NLRP3 activation threshold - Microglial NLRP3 priming creates feed-forward cycle with Aβ deposition Source: Allen Human Brain Atlas Alzheimer’s Disease Relevance: - Target genes NLRP3, CASP1, IL1B, PYCARD form the core inflammasome axis in AD neuroinflammation - Regional expression in hippocampus and cortex drives selective vulnerability of memory circuits - Inflammasome inhibition is a leading anti-inflammatory therapeutic strategy for AD This matters because expression and cell-state data narrow the plausible mechanism space. If the relevant transcripts are enriched in the exact neurons, glia, or regional compartments that show vulnerability, confidence should rise. If expression is diffuse or obviously compensatory, the intervention strategy may need to target timing or state rather than bulk abundance. Within neurodegeneration, the working model should be treated as a circuit of stress propagation. Perturbation of NLRP3, CASP1, IL1B, PYCARD or Gut-brain axis TLR4/NF-κB priming of NLRP3 inflammasome in microglia is unlikely to matter in isolation. Instead, it probably shifts the balance between adaptive compensation and maladaptive persistence. If the intervention succeeds, downstream consequences should include cleaner biomarker separation, improved cellular resilience, reduced inflammatory spillover, or better maintenance of synaptic and metabolic programs. If it fails, the most likely explanations are that the target sits too far downstream to redirect the disease, or that the disease phenotype is heterogeneous enough that a single-axis intervention only helps a subset of states. ## Evidence Supporting the Hypothesis 1. Gut microbiota-derived metabolites activate NLRP3 inflammasome in microglia, promoting neuroinflammation in AD mouse models. Identifier 33875891. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan. 2. Periodontal pathogen P. gingivalis and its gingipains detected in AD brains, with NLRP3 inflammasome activation in associated microglia. Identifier 30610225. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan. 3. NLRP3 inflammasome activation in microglia drives tau hyperphosphorylation and aggregation via ASC speck seeding. Identifier 31748742. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan. 4. Bacterial amyloids from gut microbiota cross-seed Aβ aggregation and prime NLRP3 inflammasome in TLR2-dependent manner. Identifier 27519954. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan. 5. Fecal microbiota transplant from AD patients to germ-free mice induces neuroinflammation and NLRP3-dependent cognitive impairment. Identifier 33741860. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan. 6. Gut-derived short-chain fatty acids regulate microglial inflammasome priming; dysbiosis reduces protective butyrate levels. Identifier 31043694. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan. ## Contradictory Evidence, Caveats, and Failure Modes 1. NLRP3 inflammasome also serves protective antimicrobial functions in the CNS; complete inhibition may increase infection susceptibility. Identifier 32404631. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients. 2. Blood-brain barrier limits microbial products from reaching CNS; gut-brain inflammasome priming may be an indirect rather than direct mechanism. Identifier 31043694. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients. 3. P. gingivalis detection in AD brains may reflect post-mortem artifact rather than causal pathology. Identifier 31278369. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients. 4. Microbiome composition is highly variable between individuals; identifying universal therapeutic targets for prevention is challenging. Identifier 34497383. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients. 5. Long-term NLRP3 inhibition may impair peripheral innate immune surveillance and increase cancer risk. Identifier 31337621. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients. ## Clinical and Translational Relevance From a translational perspective, this hypothesis only matters if it can be turned into a selection rule for experiments, biomarkers, or patient stratification. The row currently records market price 0.9141, debate count 1, citations 34, predictions 2, and falsifiability flag 1. Those metadata do not prove correctness, but they do show whether the idea has attracted scrutiny and whether it is accumulating the structure needed for Exchange-layer decisions. 1. Trial context: Unknown. This matters because clinical development data often reveal whether a mechanism fails on exposure, delivery, safety, or patient heterogeneity rather than on target biology alone. 2. Trial context: Unknown. This matters because clinical development data often reveal whether a mechanism fails on exposure, delivery, safety, or patient heterogeneity rather than on target biology alone. 3. Trial context: Unknown. This matters because clinical development data often reveal whether a mechanism fails on exposure, delivery, safety, or patient heterogeneity rather than on target biology alone. For Exchange-layer use, the description must specify not only why the idea may work, but also the readouts that would force a repricing. A description that never names disconfirming evidence is not investable science; it is marketing copy. ## Experimental Predictions and Validation Strategy First, the hypothesis should be decomposed into a perturbation experiment that directly manipulates NLRP3, CASP1, IL1B, PYCARD in a model matched to neurodegeneration. The key readout should include pathway markers, cell-state markers, and at least one phenotype that maps onto “Gut Microbiome Remodeling to Prevent Systemic NLRP3 Priming in Neurodegeneration”. Second, the study design should include a rescue arm. If the mechanism is causal, reversing the perturbation should recover the downstream phenotype rather than only dampening a late stress marker. Third, contradictory evidence should be operationalized prospectively with negative controls, pre-registered null thresholds, and an orthogonal assay so the description remains genuinely falsifiable instead of self-sealing. Fourth, translational relevance should be checked in human-derived material where possible, because many neurodegeneration programs look compelling in rodent systems and then collapse when the cell-state context shifts in patient tissue. ## Decision-Oriented Summary In summary, the operational claim is that targeting NLRP3, CASP1, IL1B, PYCARD within the disease frame of neurodegeneration can produce a measurable change in mechanism rather than only a cosmetic change in a terminal biomarker. The supporting evidence on the row suggests there is enough signal to justify deeper experimental work, while the contradictory evidence makes it clear that translational success will depend on choosing the right compartment, timing, and patient subset. This expanded description is therefore meant to function as working scientific context: a compact debate artifact becomes a more explicit research program with mechanistic rationale, failure modes, and criteria for updating confidence.” Framed more explicitly, the hypothesis centers NLRP3, CASP1, IL1B, PYCARD within the broader disease setting of neurodegeneration. The row currently records status proposed, origin gap_debate, and mechanism category neuroinflammation. That combination matters because thin descriptions tend to hide the causal chain that connects upstream perturbation, intermediate cell-state transition, and downstream clinical effect. The purpose of this expansion is to make those assumptions visible enough that the hypothesis can be debated, tested, and repriced instead of merely admired as an interesting sentence.
The decision-relevant question is whether modulating NLRP3, CASP1, IL1B, PYCARD or the surrounding pathway space around Gut-brain axis TLR4/NF-κB priming of NLRP3 inflammasome in microglia can redirect a disease process rather than merely decorate it with a biomarker change. In neurodegeneration, that usually means changing proteostasis, inflammatory tone, lipid handling, mitochondrial resilience, synaptic stability, or cell-state transitions in vulnerable neurons and glia. A useful description therefore has to identify where the intervention acts first, what compensatory programs are likely to respond, and what outcome would count as a mechanistic miss rather than a partial win.
SciDEX scoring currently records confidence 0.69, mechanistic plausibility 0.80, and clinical relevance 0.04.
Molecular and Cellular Rationale
The nominated target genes are NLRP3, CASP1, IL1B, PYCARD and the pathway label is Gut-brain axis TLR4/NF-κB priming of NLRP3 inflammasome in microglia. Strong mechanistic hypotheses in brain disease rarely depend on a single isolated molecular node. Instead, they work when a node sits near a control bottleneck, integrates multiple stress signals, or stabilizes a disease-relevant state transition. That is the standard this hypothesis should be held to. The claim is not simply that the target is interesting, but that it occupies leverage over a process that otherwise drifts toward persistence, toxicity, or failed repair.
Gene-expression context on the row adds an important constraint: Gene Expression Context NLRP3 (NLR Family Pyrin Domain Containing 3): - Innate immune sensor; forms inflammasome complex with ASC (PYCARD) and pro-caspase-1 - Allen Human Brain Atlas: primarily expressed in microglia; low in neurons and astrocytes - NLRP3 expression increases 3-5× in AD microglia surrounding amyloid plaques - Activated by Aβ fibrils, tau aggregates, ROS, and extracellular ATP - NLRP3 knockout mice crossed with APP/PS1 show 50% reduced plaque burden and preserved cognition - MCC950 (NLRP3 inhibitor) rescues spatial memory in AD mouse models CASP1 (Caspase-1): - Inflammatory caspase; effector protease of the inflammasome - Cleaves pro-IL-1β and pro-IL-18 into mature inflammatory cytokines - Allen Human Brain Atlas: expressed in microglia and monocyte-derived macrophages in brain - Active caspase-1 detected in AD hippocampus by immunohistochemistry; correlates with CDR score - Also cleaves gasdermin D (GSDMD) to form membrane pores → pyroptotic cell death - VX-765 (caspase-1 inhibitor) reduces Aβ burden and inflammation in J20 mice IL1B (Interleukin-1β): - Pro-inflammatory cytokine; central mediator of neuroinflammation in AD - Allen Human Brain Atlas: induced expression in microglia; minimal constitutive expression - IL-1β elevated 2-6× in AD brain, CSF, and plasma - Drives tau phosphorylation via p38-MAPK and activates astrocytic A1 neurotoxic phenotype - Chronic IL-1β exposure impairs hippocampal LTP and reduces BDNF expression - Anti-IL-1β therapy (canakinumab) reduced dementia incidence in CANTOS cardiovascular trial PYCARD (ASC / Apoptosis-Associated Speck-like Protein): - Adaptor protein; bridges NLRP3 sensor to caspase-1 effector via CARD-CARD interaction - ASC specks released from pyroptotic microglia propagate inflammation to neighboring cells - ASC specks cross-seed Aβ aggregation — direct molecular link between inflammation and amyloidosis - Extracellular ASC detectable in AD CSF; proposed as inflammatory biomarker Microbial Inflammasome Priming: - Gut microbiome-derived molecules (LPS, short-chain fatty acids) prime NLRP3 via NF-κB signal 1 - Dysbiosis in AD patients increases circulating LPS, lowering NLRP3 activation threshold - Microglial NLRP3 priming creates feed-forward cycle with Aβ deposition Source: Allen Human Brain Atlas Alzheimer’s Disease Relevance: - Target genes NLRP3, CASP1, IL1B, PYCARD form the core inflammasome axis in AD neuroinflammation - Regional expression in hippocampus and cortex drives selective vulnerability of memory circuits - Inflammasome inhibition is a leading anti-inflammatory therapeutic strategy for AD This matters because expression and cell-state data narrow the plausible mechanism space. If the relevant transcripts are enriched in the exact neurons, glia, or regional compartments that show vulnerability, confidence should rise. If expression is diffuse or obviously compensatory, the intervention strategy may need to target timing or state rather than bulk abundance.
Within neurodegeneration, the working model should be treated as a circuit of stress propagation. Perturbation of NLRP3, CASP1, IL1B, PYCARD or Gut-brain axis TLR4/NF-κB priming of NLRP3 inflammasome in microglia is unlikely to matter in isolation. Instead, it probably shifts the balance between adaptive compensation and maladaptive persistence. If the intervention succeeds, downstream consequences should include cleaner biomarker separation, improved cellular resilience, reduced inflammatory spillover, or better maintenance of synaptic and metabolic programs. If it fails, the most likely explanations are that the target sits too far downstream to redirect the disease, or that the disease phenotype is heterogeneous enough that a single-axis intervention only helps a subset of states.
Evidence Supporting the Hypothesis
- Gut microbiota-derived metabolites activate NLRP3 inflammasome in microglia, promoting neuroinflammation in AD mouse models. Identifier 33875891. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
- Periodontal pathogen P. gingivalis and its gingipains detected in AD brains, with NLRP3 inflammasome activation in associated microglia. Identifier 30610225. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
- NLRP3 inflammasome activation in microglia drives tau hyperphosphorylation and aggregation via ASC speck seeding. Identifier 31748742. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
- Bacterial amyloids from gut microbiota cross-seed Aβ aggregation and prime NLRP3 inflammasome in TLR2-dependent manner. Identifier 27519954. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
- Fecal microbiota transplant from AD patients to germ-free mice induces neuroinflammation and NLRP3-dependent cognitive impairment. Identifier 33741860. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
- Gut-derived short-chain fatty acids regulate microglial inflammasome priming; dysbiosis reduces protective butyrate levels. Identifier 31043694. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
Contradictory Evidence, Caveats, and Failure Modes
- NLRP3 inflammasome also serves protective antimicrobial functions in the CNS; complete inhibition may increase infection susceptibility. Identifier 32404631. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.
- Blood-brain barrier limits microbial products from reaching CNS; gut-brain inflammasome priming may be an indirect rather than direct mechanism. Identifier 31043694. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.
- P. gingivalis detection in AD brains may reflect post-mortem artifact rather than causal pathology. Identifier 31278369. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.
- Microbiome composition is highly variable between individuals; identifying universal therapeutic targets for prevention is challenging. Identifier 34497383. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.
- Long-term NLRP3 inhibition may impair peripheral innate immune surveillance and increase cancer risk. Identifier 31337621. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.
Clinical and Translational Relevance
From a translational perspective, this hypothesis only matters if it can be turned into a selection rule for experiments, biomarkers, or patient stratification. The row currently records market price 0.9141, debate count 1, citations 34, predictions 2, and falsifiability flag 1. Those metadata do not prove correctness, but they do show whether the idea has attracted scrutiny and whether it is accumulating the structure needed for Exchange-layer decisions.
- Trial context: Unknown. This matters because clinical development data often reveal whether a mechanism fails on exposure, delivery, safety, or patient heterogeneity rather than on target biology alone.
- Trial context: Unknown. This matters because clinical development data often reveal whether a mechanism fails on exposure, delivery, safety, or patient heterogeneity rather than on target biology alone.
- Trial context: Unknown. This matters because clinical development data often reveal whether a mechanism fails on exposure, delivery, safety, or patient heterogeneity rather than on target biology alone. For Exchange-layer use, the description must specify not only why the idea may work, but also the readouts that would force a repricing. A description that never names disconfirming evidence is not investable science; it is marketing copy.
Experimental Predictions and Validation Strategy
First, the hypothesis should be decomposed into a perturbation experiment that directly manipulates NLRP3, CASP1, IL1B, PYCARD in a model matched to neurodegeneration. The key readout should include pathway markers, cell-state markers, and at least one phenotype that maps onto “Gut Microbiome Remodeling to Prevent Systemic NLRP3 Priming in Neurodegeneration”. Second, the study design should include a rescue arm. If the mechanism is causal, reversing the perturbation should recover the downstream phenotype rather than only dampening a late stress marker. Third, contradictory evidence should be operationalized prospectively with negative controls, pre-registered null thresholds, and an orthogonal assay so the description remains genuinely falsifiable instead of self-sealing. Fourth, translational relevance should be checked in human-derived material where possible, because many neurodegeneration programs look compelling in rodent systems and then collapse when the cell-state context shifts in patient tissue.
Decision-Oriented Summary
In summary, the operational claim is that targeting NLRP3, CASP1, IL1B, PYCARD within the disease frame of neurodegeneration can produce a measurable change in mechanism rather than only a cosmetic change in a terminal biomarker. The supporting evidence on the row suggests there is enough signal to justify deeper experimental work, while the contradictory evidence makes it clear that translational success will depend on choosing the right compartment, timing, and patient subset. This expanded description is therefore meant to function as working scientific context: a compact debate artifact becomes a more explicit research program with mechanistic rationale, failure modes, and criteria for updating confidence.
Evidence for (26)
Gut microbiota-derived metabolites activate NLRP3 inflammasome in microglia, promoting neuroinflammation in AD mouse models.
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
Periodontal pathogen P. gingivalis and its gingipains detected in AD brains, with NLRP3 inflammasome activation in associated microglia.
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.
NLRP3 inflammasome activation in microglia drives tau hyperphosphorylation and aggregation via ASC speck seeding.
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
Bacterial amyloids from gut microbiota cross-seed Aβ aggregation and prime NLRP3 inflammasome in TLR2-dependent manner.
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
Fecal microbiota transplant from AD patients to germ-free mice induces neuroinflammation and NLRP3-dependent cognitive impairment.
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
Gut-derived short-chain fatty acids regulate microglial inflammasome priming; dysbiosis reduces protective butyrate levels.
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
MCC950, a selective NLRP3 inhibitor, reduces Aβ accumulation and rescues cognitive function in APP/PS1 mice.
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
Oral antibiotic cocktail reduces microglial NLRP3 activation and amyloid plaque burden in 5xFAD mice via gut-brain axis modulation.
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
Helicobacter pylori infection associated with increased AD risk in meta-analysis of 11 studies; eradication reduces cognitive decline trajectory.
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
Caspase-1 (CASP1) cleaves IL-1β and IL-18 downstream of NLRP3; genetic deletion of CASP1 is neuroprotective in tau transgenic mice.
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
Trained immunity of microglia by peripheral infection leads to sustained NLRP3 inflammasome priming and accelerated neurodegeneration months after infection resolution.
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
Elevated expression of the NLRP3 inflammasome in post-mortem brain white matter and immune cells in multiple sclerosis.
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
NLRP3 Inflammasome and Polycystic Ovary Syndrome (PCOS): A Novel Profile in Adipose Tissue.
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
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.
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
Nlrc4 Inflammasome Expression After Acute Myocardial Infarction in Rats.
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
USP5 attenuates NLRP3 inflammasome activation by promoting autophagic degradation of NLRP3
USP22 suppresses the NLRP3 inflammasome by degrading NLRP3 via ATG5-dependent autophagy
Small molecule-driven NLRP3 inflammation inhibition via interplay between ubiquitination and autophagy: implications for Parkinson disease
The macrophage-specific V-ATPase subunit ATP6V0D2 restricts inflammasome activation and bacterial infection by facilitating autophagosome-lysosome fusion
Andrographolide Attenuates NLRP3 Inflammasome Activation and Airway Inflammation in Exacerbation of Chronic Obstructive Pulmonary Disease
Berberine Protects Against NLRP3 Inflammasome via Ameliorating Autophagic Impairment in MPTP-Induced Parkinson's Disease Model.
Inflammasome and toll-like receptor signaling in human monocytes after successful cardiopulmonary resuscitation.
Small molecule-driven mitophagy-mediated NLRP3 inflammasome inhibition is responsible for the prevention of colitis-associated cancer.
SCFA-producing bacteria depletion is associated with elevated serum LPS and IL-1β levels in early-stage Alzheimer's patients.
Restoration of SCFA production by Akkermansia and Faecalibacterium species strengthens intestinal barrier function, reducing bacterial LPS translocation into systemic circulation.
NLRP3 inflammasome activation in microglia drives blood-brain barrier dysfunction and progressive neurodegeneration through sustained cytokine production and oxidative stress.
Evidence against (11)
NLRP3 inflammasome also serves protective antimicrobial functions in the CNS; complete inhibition may increase infection susceptibility.
Blood-brain barrier limits microbial products from reaching CNS; gut-brain inflammasome priming may be an indirect rather than direct mechanism.
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
P. gingivalis detection in AD brains may reflect post-mortem artifact rather than causal pathology.
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
Microbiome composition is highly variable between individuals; identifying universal therapeutic targets for prevention is challenging.
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.
Long-term NLRP3 inhibition may impair peripheral innate immune surveillance and increase cancer risk.
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
Triptolide prevents LPS-induced skeletal muscle atrophy via inhibiting NF-κB/TNF-α and regulating protein synthesis/degradation pathway
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
Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice
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
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
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
The NLRP3-inflammasome inhibitor MCC950 improves cardiac function in a HFpEF mouse model
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
Sepsis and the Liver
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
Bone marrow vacuolization to curative strategies: Evolving paradigms in VEXAS syndrome management
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