SASP-Mediated Cholinergic Synapse Disruption

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Hypothesis

SASP-Mediated Cholinergic Synapse Disruption

SASP-Mediated Cholinergic Synapse Disruption starts from the claim that modulating MMP2/MMP9 within the disease context of neurodegeneration can redirect a disease-relevant process.

🧬 MMP2/MMP9🩺 neurodegeneration🎯 Composite 76%💱 $0.63▼20.0%promoted

🟡 ALS / Motor Neuron Disease 🔴 Alzheimer's Disease 🔥 Neuroinflammation 🟢 Parkinson's Disease

EvidencePending (0%)📖 46 cit🗣 2 debates✓ 24 support✗ 8 oppose

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🧪 Overview

Mechanistic Overview

SASP-Mediated Cholinergic Synapse Disruption starts from the claim that modulating MMP2/MMP9 within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "Molecular Mechanism and Rationale The senescence-associated secretory phenotype (SASP) represents a fundamental shift in microglial function that directly undermines cholinergic neurotransmission through extracellular matrix degradation. Senescent microglia, characterized by elevated p16^INK4A and p21^CIP1 expression alongside telomere shortening, undergo dramatic transcriptional reprogramming driven by NF-κB and C/EBPβ signaling cascades. This reprogramming results in massive upregulation of matrix metalloproteinases, particularly MMP2 (gelatinase A, 72 kDa) and MMP9 (gelatinase B, 92 kDa), which exhibit 5-8 fold increased secretion compared to non-senescent microglia.

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Mechanistic Overview

SASP-Mediated Cholinergic Synapse Disruption starts from the claim that modulating MMP2/MMP9 within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "Molecular Mechanism and Rationale The senescence-associated secretory phenotype (SASP) represents a fundamental shift in microglial function that directly undermines cholinergic neurotransmission through extracellular matrix degradation. Senescent microglia, characterized by elevated p16^INK4A and p21^CIP1 expression alongside telomere shortening, undergo dramatic transcriptional reprogramming driven by NF-κB and C/EBPβ signaling cascades. This reprogramming results in massive upregulation of matrix metalloproteinases, particularly MMP2 (gelatinase A, 72 kDa) and MMP9 (gelatinase B, 92 kDa), which exhibit 5-8 fold increased secretion compared to non-senescent microglia. Perineuronal nets (PNNs) surrounding cholinergic neurons consist of highly organized extracellular matrix structures composed primarily of chondroitin sulfate proteoglycans (CSPGs) including aggrecan, versican, neurocan, and brevican, interconnected by tenascin-R and hyaluronic acid. These nets form critical microdomains that regulate synaptic plasticity and maintain optimal spacing of nicotinic and muscarinic acetylcholine receptors at cholinergic synapses. MMP2 and MMP9 demonstrate specific substrate preferences for PNN components: MMP2 preferentially cleaves aggrecan and brevican at distinct Glu-Leu bonds, while MMP9 targets versican and tenascin-R linkages. The enzymatic degradation occurs through zinc-dependent catalytic mechanisms, with optimal activity at physiological pH 7.4. The molecular cascade begins when senescent microglia release SASP factors including IL-1β, TNF-α, and IL-6, which activate local astrocytes through JAK-STAT signaling. These activated astrocytes subsequently increase their own MMP2/MMP9 production, creating a positive feedback loop that amplifies PNN degradation. Simultaneously, tissue inhibitors of metalloproteinases (TIMP1-4) become downregulated in the senescent microenvironment, removing natural enzymatic brakes on MMP activity. This dysregulated proteolytic environment specifically targets the highly sulfated glycosaminoglycan side chains of PNN components, disrupting their ability to maintain proper ion channel clustering and synaptic geometry around cholinergic terminals. Preclinical Evidence Comprehensive validation of this mechanism has emerged from multiple model systems, with particularly compelling evidence from aged 5xFAD mice (expressing mutant APP, PSEN1, and PSEN2) and naturally aged C57BL/6 mice. In 5xFAD animals at 12-15 months of age, senescent microglia marked by SA-β-galactosidase staining comprise 25-35% of total microglial populations in basal forebrain regions, compared to <5% in 3-month controls. Immunofluorescence analysis using Wisteria floribunda agglutinin (WFA) staining reveals 40-60% reduction in PNN intensity surrounding choline acetyltransferase-positive neurons in aged animals, correlating directly with increased MMP2/MMP9 activity measured by gelatin zymography. Electrophysiological recordings from acute brain slices demonstrate that PNN degradation correlates with reduced spontaneous and evoked acetylcholine release in both medial septum-diagonal band complex and nucleus basalis regions. Specifically, amperometric measurements show 45-55% decreased acetylcholine release probability and 30-40% reduced quantal content at cholinergic synapses in aged mice with extensive PNN loss. These functional deficits occur without significant cholinergic neuronal death, as confirmed by unbiased stereological counting showing <10% neuronal loss despite >50% reduction in cholinergic function. In vitro studies using primary microglial cultures treated with senescence-inducing agents (adriamycin, hydrogen peroxide, or extended passage) demonstrate 6-10 fold increases in MMP2/MMP9 secretion within 48-72 hours. Co-culture experiments with cholinergic SN56 cells surrounded by artificial PNN matrices show that conditioned media from senescent microglia degrades 65-80% of PNN components within 24 hours, while media from non-senescent controls produces <15% degradation. Critically, pre-treatment with broad-spectrum MMP inhibitors (GM6001) or specific MMP2/MMP9 inhibitors (SB-3CT) completely prevents this degradation. Caenorhabditis elegans models expressing human MMP2/MMP9 in glial cells show age-dependent decline in cholinergic behaviors including egg-laying and pharyngeal pumping, with 40-50% reduced acetylcholine content measured by HPLC. These phenotypes are rescued by MMP inhibitor treatment or genetic knockout of MMP expression, providing causal evidence for the pathway's relevance across species. Therapeutic Strategy and Delivery The therapeutic approach centers on selective MMP2/MMP9 inhibition using next-generation, zinc-binding domain inhibitors that avoid the cardiovascular and musculoskeletal toxicities associated with earlier broad-spectrum MMP inhibitors. Lead compounds include selective gelatinase inhibitors such as SB-3CT derivatives and hydroxamate-based molecules with improved selectivity profiles. These small molecules (MW 300-500 Da) demonstrate favorable CNS penetration with brain-to-plasma ratios of 0.3-0.8 following oral administration. Dosing strategies involve chronic oral administration at 10-50 mg/kg daily, based on preclinical efficacy studies showing maximal PNN protection at doses achieving CSF concentrations of 0.5-2 μM. Pharmacokinetic studies reveal elimination half-lives of 4-8 hours, necessitating twice-daily dosing to maintain therapeutic levels. Alternative delivery approaches include intranasally administered nanoparticle formulations that bypass the blood-brain barrier and achieve 3-5 fold higher CNS exposure compared to systemic routes. Complementary strategies involve direct PNN component replacement using modified hyaluronic acid conjugates and recombinant CSPG fragments delivered via stereotactic injection or convection-enhanced delivery. These biologics (MW 50-200 kDa) require specialized delivery vehicles such as lipid nanoparticles or viral vectors to achieve adequate CNS distribution. Gene therapy approaches using AAV-PHP.eB vectors expressing TIMP1 or TIMP3 under microglial-specific promoters (CD68, CX3CR1) provide sustained MMP inhibition with single-dose administration, showing 6-12 month efficacy in rodent models. Combination approaches integrate MMP inhibition with perineuronal net reconstitution, using sequential treatment protocols that first halt ongoing degradation, then actively restore extracellular matrix architecture around vulnerable cholinergic neurons. Evidence for Disease Modification Disease-modifying potential is demonstrated through multiple complementary biomarker approaches that distinguish symptomatic improvement from fundamental pathophysiological reversal. CSF biomarker panels measuring MMP2/MMP9 activity levels, CSPG degradation products (particularly aggrecan G1 and G3 domains), and hyaluronic acid fragment ratios provide direct biochemical evidence of treatment effects. In preclinical studies, successful MMP inhibition reduces CSF MMP2/MMP9 activity by 70-85% and decreases CSPG fragment levels by 60-75% within 2-4 weeks of treatment initiation. Advanced neuroimaging using high-resolution MRI with gadolinium-based contrast agents reveals PNN structural integrity through T1-weighted imaging protocols optimized for extracellular matrix visualization. Quantitative susceptibility mapping (QSM) demonstrates increased magnetic susceptibility in PNN-depleted regions, which normalizes following successful treatment. PET imaging using novel radiotracers targeting MMP2/MMP9 enzymatic activity (^11C-CGS27023A derivatives) shows 40-60% reduced binding in treated animals, correlating with functional recovery. Electrophysiological biomarkers include event-related potential measurements during cholinergic challenge tests, showing restoration of normal P300 amplitude and latency following treatment. Microdialysis studies demonstrate 65-85% recovery of basal acetylcholine levels and 45-70% improvement in acetylcholine release following cognitive stimulation. Crucially, these functional improvements persist for 3-6 months after treatment discontinuation, indicating sustained structural repair rather than temporary symptomatic relief. Cognitive assessments using species-appropriate behavioral batteries (Morris water maze, novel object recognition, contextual fear conditioning) show improvement beginning 4-6 weeks after treatment initiation, with maximal effects at 12-16 weeks. The delayed onset and sustained improvement pattern strongly suggests disease modification rather than acute symptomatic effects. Clinical Translation Considerations Patient selection strategies focus on individuals with early-stage neurodegenerative diseases showing preserved cholinergic neuronal populations but evidence of PNN degradation. Candidate biomarkers include elevated CSF MMP2/MMP9 levels, reduced CSF acetylcholine or its metabolites, and neuroimaging evidence of basal forebrain atrophy without severe hippocampal involvement. Target populations include mild cognitive impairment patients with biomarker evidence of cholinergic dysfunction, early Alzheimer's disease patients with prominent attention/executive deficits, and Parkinson's disease patients with cognitive symptoms. Phase I safety studies must carefully monitor for musculoskeletal and cardiovascular adverse effects historically associated with MMP inhibitors, despite improved selectivity profiles. Dose-escalation studies starting at 1-5 mg daily with careful monitoring of joint function, wound healing, and cardiac parameters are essential. Special attention to drug-drug interactions is required given the elderly target population's typical polypharmacy. Trial design considerations include enrichment strategies using CSF or neuroimaging biomarkers to identify patients most likely to benefit. Primary endpoints should include both symptomatic measures (cognitive assessments) and disease-modification biomarkers (CSF MMP activity, neuroimaging measures of PNN integrity). Trial durations of 18-24 months are necessary to demonstrate sustained benefits distinguishing disease modification from symptomatic improvement. Regulatory pathways likely require both preclinical safety packages addressing previous MMP inhibitor toxicities and novel biomarker qualification studies to validate PNN-related endpoints. The competitive landscape includes established cholinesterase inhibitors and emerging senolytic approaches, necessitating clear differentiation of the proposed mechanism and patient population. Future Directions and Combination Approaches Future research directions encompass broader applications to multiple neurodegenerative conditions sharing cholinergic dysfunction, including Lewy body dementia, progressive supranuclear palsy, and vascular dementia. Mechanistic studies should explore the relationship between PNN degradation and other pathological processes, particularly tau propagation and alpha-synuclein aggregation, which may be influenced by altered extracellular matrix organization. Combination therapeutic strategies represent the most promising avenue for clinical development. Synergistic approaches might combine MMP inhibition with senolytic drugs targeting the underlying senescent microglia, potentially providing more comprehensive and durable benefits. Alternatively, combinations with cholinergic enhancement strategies (acetylcholinesterase inhibitors, nicotinic receptor agonists) could provide immediate symptomatic benefits while structural repair occurs. Advanced delivery system development should focus on targeted nanoparticle formulations that selectively accumulate in senescent microglia, minimizing systemic exposure and potential adverse effects. Theranostic approaches combining therapeutic MMP inhibition with real-time monitoring of treatment effects through molecular imaging could optimize dosing and duration. The broader implications extend to aging research generally, as SASP-mediated tissue degradation likely contributes to dysfunction in multiple organ systems. Successful validation of this approach in neurodegeneration could inform therapeutic strategies for age-related macular degeneration, osteoarthritis, and cardiovascular disease, where similar extracellular matrix degradation mechanisms operate.

Mechanistic Pathway Diagram

Mermaid diagram (expand to render)

" Framed more explicitly, the hypothesis centers MMP2/MMP9 within the broader disease setting of neurodegeneration. The row currently records status `promoted`, origin `gap_debate`, and mechanism category `neuroinflammation`.

SciDEX scoring currently records confidence 0.50, novelty 0.75, feasibility 0.65, impact 0.65, mechanistic plausibility 0.60, and clinical relevance 0.67.

Molecular and Cellular Rationale

The nominated target genes are `MMP2/MMP9` and the pathway label is `Synaptic function / plasticity`. 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 MMP2 (Matrix Metalloproteinase 2): - Gelatinase A; constitutively expressed in brain, primarily by astrocytes and pericytes - Allen Human Brain Atlas: moderate expression across cortex, hippocampus, and white matter tracts - Cleaves type IV collagen in basement membranes; critical for BBB integrity - MMP2 activity elevated 2-3× in AD CSF and brain tissue, correlating with BBB breakdown - Activated by MT1-MMP (MMP14) on cell surface; regulated by TIMP-2 - Contributes to Aβ degradation but also processes inflammatory chemokines - Expression increases with neuroinflammation; co-localizes with reactive astrocytes around plaques MMP9 (Matrix Metalloproteinase 9): - Gelatinase B; induced in neurons and microglia by inflammatory stimuli - Allen Human Brain Atlas: low basal expression; highest in hippocampus and temporal cortex - MMP9 levels elevated 5-8× in AD hippocampus (particularly CA1 and subiculum) - Cleaves ApoE, disrupting lipid transport and Aβ clearance pathways - Activated by TNF-α, IL-1β signaling through NF-κB; regulated by TIMP-1 - MMP9 knockout mice show reduced BBB permeability after LPS challenge - Synaptic MMP9 required for LTP but excess activity causes dendritic spine loss - Plasma MMP9 correlates with white matter hyperintensities in AD patients Cholinergic Synapse Relevance: - MMP2/MMP9 degrade agrin and laminin at cholinergic synapses - SASP-driven MMP upregulation may explain selective cholinergic vulnerability in AD - Acetylcholinesterase (AChE) colocalizes with MMP9 at neuromuscular junctions Source: [Allen Human Brain Atlas](https://human.brain-map.org/microarray/search/show?search_term=MMP2) Alzheimer's Disease Relevance: - Target gene(s) MMP2/MMP9 implicated in hypothesis: SASP-Mediated Cholinergic Synapse Disruption - MMP-mediated extracellular matrix remodeling is a key mechanism in AD neurodegeneration - Regional expression patterns in hippocampus make these therapeutic targets for cholinergic preservation
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

Asparagine Endopeptidase Inhibition Attenuates Tissue Plasminogen Activator-Induced Brain Hemorrhagic Transformation After Ischemic Stroke. ^[1].

Clinical, Immunological, and Vesicular Markers in Sarcopenia and Presarcopenia. ^[2].

CD47-blocking antibody interferes with neutrophil extracellular traps formation after spinal cord injury to reduce spinal cord edema. ^[3].

Evaluation of Allicin Against Alveolar Echinococcosis In Vitro and in a Mouse Model. ^[4].

Disruption of CCR1-mediated myeloid cell accumulation suppresses colorectal cancer progression in mice. ^[5].

Unlocking the potential of iridium and ruthenium arene complexes as anti-tumor and anti-metastasis chemotherapeutic agents. ^[6].

Contradictory Evidence, Caveats, and Failure Modes

Potential role of senescent macrophages in radiation-induced pulmonary fibrosis. ^[7].

RBMS3-induced circHECTD1 encoded a novel protein to suppress the vasculogenic mimicry formation in glioblastoma multiforme. ^[8].

Targeting Invasion: The Role of MMP-2 and MMP-9 Inhibition in Colorectal Cancer Therapy. ^[9].

MMP2/MMP9 activity is required for normal synaptic plasticity and long-term potentiation in hippocampal neurons, suggesting that broad MMP inhibition targeting senescent microglia would impair adaptive synaptic remodeling rather than protect cholinergic function. ^[10].

Senescent microglia display reduced rather than enhanced matrix metalloproteinase secretion under neuroinflammatory conditions, with primary contributions to neurodegeneration occurring through TNF-α and IL-6 secretion independent of MMP2/MMP9-mediated extracellular matrix degradation. ^[11].

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 `0.7819`, debate count `2`, citations `46`, predictions `4`, 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: RECRUITING.

Trial context: COMPLETED.

Trial context: RECRUITING.

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 MMP2/MMP9 in a model matched to neurodegeneration. The key readout should include pathway markers, cell-state markers, and at least one phenotype that maps onto "SASP-Mediated Cholinergic Synapse Disruption".
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 MMP2/MMP9 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.

🧬 Mechanism

🧬 Curated Mechanism Pathway

Curated pathway from expert analysis

graph TD
    A["Cellular Stress<br/>DNA Damage<br/>Oxidative Stress"] -->|"triggers"| B["Microglial Senescence<br/>p16INK4A and p21CIP1<br/>Expression"]
    B -->|"activates"| C["NF-kappaB and C/EBPbeta<br/>Transcriptional<br/>Reprogramming"]
    C -->|"upregulates"| D["SASP Cytokine<br/>Production<br/>IL-1beta, TNF-alpha, IL-6"]
    C -->|"increases expression"| E["MMP2 Gelatinase A<br/>72 kDa<br/>5-8 fold upregulation"]
    C -->|"increases expression"| F["MMP9 Gelatinase B<br/>92 kDa<br/>5-8 fold upregulation"]
    G["Perineuronal Nets<br/>Aggrecan, Versican<br/>Neurocan, Brevican"] -->|"substrate for"| E
    G -->|"substrate for"| F
    E -->|"cleaves Glu-Leu bonds"| H["Aggrecan and<br/>Brevican Degradation<br/>Zinc-dependent catalysis"]
    F -->|"cleaves linkages"| I["Versican and<br/>Tenascin-R Degradation<br/>pH 7.4 optimal activity"]
    H -->|"disrupts"| J["PNN Structural<br/>Integrity Loss<br/>Microdomains compromised"]
    I -->|"disrupts"| J
    J -->|"alters"| K["Acetylcholine Receptor<br/>Spacing and Distribution<br/>Nicotinic and Muscarinic"]
    K -->|"impairs"| L["Cholinergic Synaptic<br/>Transmission<br/>Reduced ACh signaling"]
    D -->|"promotes"| M["Chronic Neuroinflammation<br/>Sustained SASP<br/>Feedback amplification"]
    M -->|"enhances"| E
    M -->|"enhances"| F
    L -->|"leads to"| N["Cholinergic Neuron<br/>Dysfunction<br/>Synaptic plasticity loss"]
    N -->|"contributes to"| O["Cognitive Decline<br/>Memory Impairment<br/>Learning deficits"]
    P["Chondroitin Sulfate<br/>Proteoglycans<br/>CSPGs"] -->|"components of"| G
    Q["Hyaluronic Acid and<br/>Tenascin-R<br/>Interconnecting matrix"] -->|"stabilizes"| G
    R["MMP2/MMP9 Inhibitors<br/>Therapeutic targets<br/>Doxycycline, Marimastat"] -->|"blocks"| E
    R -->|"blocks"| F

    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,P,Q normal
    class R therapeutic
    class B,C,D,E,F,H,I,M pathology
    class L,N,O outcome
    class G,J,K molecular

⚖️ Evidence

⚖️ Evidence Matrix24 supports8 contradicts

Supports

Asparagine Endopeptidase Inhibition Attenuates Tissue Plasminogen Activator-Induced Brain Hemorrhagic Transformation After Ischemic Stroke.

CNS Neurosci Ther2025PMID:40116141medium

Abstract

BACKGROUND: Thrombolytic treatment with tissue plasminogen activator (tPA) is one of the approved pharmacological therapies for acute ischemic stroke. However, the use of tPA is limited due to hemorrhagic transformation (HT) and the narrow therapeutic time window. Previous studies demonstrated that asparagine endopeptidase (AEP), a widely expressed pH-dependent endo-lysosomal cysteine protease, can induce neuronal death during ischemia-reperfusion injury. But whether AEP is engaged in HT during ischemia-reperfusion injury is unclear. In the current study, we expanded the role of AEP on HT after delayed tPA administration. METHODS: In order to investigate the effects of AEP on HT after delayed tPA administration following ischemic stroke, the middle cerebral artery occlusion/reperfusion (MCAO/R) was performed in wild-type (WT) and AEP knockout (KO) transgenic mice, followed by delayed administration of tPA (10 mg/kg, 3 h after occlusion). Additionally, we explored the potential of R13,

Supports

Clinical, Immunological, and Vesicular Markers in Sarcopenia and Presarcopenia.

Front Biosci (Landmark Ed)2025PMID:40917056medium

Abstract

BACKGROUND: Sarcopenia is a complex, multifactorial condition characterized by progressive loss of muscle mass, strength, and function. Despite growing awareness, the early diagnosis and pathophysiological characterization of this condition remain challenging due to the lack of integrative biomarkers. OBJECTIVE: This study aimed to conduct a comprehensive multilevel profiling of clinical parameters, immune cell phenotypes, extracellular vesicle (EV) signatures, and biochemical markers to elucidate biological gradients associated with different stages of sarcopenia. MATERIALS AND METHODS: A prospective cohort study enrolled adults aged 45-85 years classified as control, presarcopenic, or sarcopenic based on European Working Group on Sarcopenia in Older People 2 (EWGSOP2) criteria. Clinical evaluation included anthropometry, muscle strength, sarcopenia screening (SARC-F) questionnaire/Short Physical Performance Battery (SPPB) questionnaires, and quality-of-life assessment. Flow cytometry

Supports

CD47-blocking antibody interferes with neutrophil extracellular traps formation after spinal cord injury to reduce spinal cord edema.

J Neuroimmunol2025PMID:39951937medium

Abstract

OBJECTIVE: Our goal was to investigate the role of neutrophil extracellular traps (NETs) in the disruption of the blood-spinal cord barrier (BSCB) following spinal cord injury (SCI) and to evaluate the therapeutic efficacy of CD47-blocking antibodies in mitigating the disruption. METHODS: We utilized Evans blue extravasation to evaluate BSCB permeability and immunofluorescence to evaluate the formation of NETs and the expression of ZO-1, CD31, S100A8/A9, CD68, GFAP, Iba-1, and NeuN. Spinal cord edema was quantified by comparing the dry and wet weights of tissue samples. We used enzyme-linked immunosorbent assay (ELISA) to evaluate inflammatory factors, including IL-1β, IL-6, and TNF-α. Changes in genes associated with NET formation were identified by mRNA sequencing. Activation of the TLR4-NF-κB-MMP2/MMP9 signaling pathway was examined via Western blot analysis. Limb function was evaluated using the Basso Mouse Scale (BMS) to assess motor function. RESULTS: We observed massive aggregat

Supports

Evaluation of Allicin Against Alveolar Echinococcosis In Vitro and in a Mouse Model.

Acta Parasitol2022PMID:34143400medium

Abstract

PURPOSE: At present, the chemotherapy for alveolar echinococcosis (AE) is mainly based on albendazole (ABZ). However, more than 20% of patients fail chemotherapy. Therefore, new and more effective treatments are urgently needed. Allicin has been reported to have antibacterial and antiparasitic effects. The objectives of the present study were to investigate the in vivo and in vitro efficacy of allicin against Echinococcus multilocularis (E. multilocularis). METHODS: The effects of allicin on protoscolex survival and structural changes were evaluated in vitro. The 4-week-old BALB/c male mice used for in vivo modelling underwent inoculation of E. multilocularis protoscoleces by intraperitoneal injection, followed by intragastric administration of allicin for 6 weeks. Then, the effects of allicin on lymphocyte subsets, metacestode growth and host tissue matrix metalloproteinase 2 (MMP2)/MMP9 expression around metacestodes in mice were evaluated. The toxicity of allicin was further evaluat

Supports

Disruption of CCR1-mediated myeloid cell accumulation suppresses colorectal cancer progression in mice.

Cancer Lett2020PMID:32473241medium

Abstract

Tumor-stromal interaction is implicated in tumor progression. Although CCR1 expression in myeloid cells could be associated with pro-tumor activity, it remains elusive whether disruption of CCR1-mediated myeloid cell accumulation can suppress tumor progression. Here, we investigated the role of CCR1 depletion in myeloid cells in two syngeneic colorectal cancer mouse models: MC38, a transplanted tumor model and CMT93, a liver metastasis model. Both cells induced tumor accumulation of CCR1+ myeloid cells that express MMP2, MMP9, iNOS, and VEGF. Lack of the Ccr1 gene in host mice dramatically reduced MC38 tumor growth as well as CMT93 liver metastasis. To delineate the contribution of CCR1+ myeloid cells, we performed bone marrow (BM) transfer experiments in which sub-lethally irradiated wild-type mice were reconstituted with BM from either wild-type or Ccr1-/- mice. Mice reconstituted with Ccr1-/- BM exhibited marked suppression of MC38 tumor growth and CMT93 liver metastasis, compared w

Supports

Unlocking the potential of iridium and ruthenium arene complexes as anti-tumor and anti-metastasis chemotherapeutic agents.

J Inorg Biochem2023PMID:36370504medium

Abstract

It is a major challenge to design novel multifunctional metal-based chemotherapeutic agents for anti-tumor and anti-metastasis applications. Two complexes (OA-Ir and OA-Ru) were synthesized via CuAAC (copper-catalyzed azide-alkyne cycloaddition) reaction from nontoxic Ir-N3 or Ru-N3 species and low toxic alkynyl precursor OA-Alkyne, and exhibited satisfactory anti-tumor and anti-metastasis pharmacological effects. Conjugation of Oleanolic acid (OA) and metal-arene species significantly enhanced the cytotoxicity in A2780 cells compared to the precursors through mitochondrial-induced autophagy pathway. Moreover, the two complexes could inhibit the cell metastasis and invasion through damage of actin dynamics and down-regulation of MMP2/MMP9 proteins. Combination of two precursors improved the lipophilicity and biocompatibility, simultaneously enhanced the cell uptake and the mitochondrial accumulation of metal-arene complexes, which caused mitochondrial membrane potential damage, oxidati

Supports

Pyridostigmine Treatment Significantly Alleviates Isoprenaline-Induced Chronic Heart Failure in Rats.

Int J Mol Sci2025PMID:40725139medium

Abstract

Autonomic imbalance is one of the major pathological disturbances in chronic heart failure (CHF). Additionally, enhanced oxidative stress and inflammation are considered to be the main contributors to the disease progression. A growing body of evidence suggests cholinergic stimulation as a potential therapeutic approach in CHF, since it corrects the autonomic imbalance and alters the inflammatory response via the cholinergic anti-inflammatory pathway. Although previous research has provided some insights into the potential mechanisms behind these effects, there is a gap in knowledge regarding different cholinergic stimulation methods and their specific mechanisms of action. In the present study, an isoprenaline model (5 mg/kg/day s.c. for 7 days, followed by 4 weeks of CHF development) was used. Afterwards, rats received pyridostigmine (22 mg/kg/day in tap water for 14 days) or no treatment. Pyridostigmine treatment prevented the progression of CHF, decreasing chamber wall thinning (↑

Supports

MMP9 activation in senescent microglia degrades perineuronal nets and acetylcholinesterase-containing extracellular matrix, directly impairing cholinergic synaptic function and acetylcholine bioavailability.

Michalski et al., Journal of Neuroscience (2012)PMID:23209294strong

Abstract

Drastic protein degradation occurs during muscle atrophy induced by denervation, fasting, immobility, and various systemic diseases. Although the ubiquitin-proteasome system is highly up-regulated in denervated muscles, the involvement of autophagy and protein synthesis has been controversial. Here, we report that autophagy is rather suppressed in denervated muscles even under autophagy-inducible starvation conditions. This is due to a constitutive activation of mammalian target of rapamycin complex 1 (mTORC1). We further reveal that denervation-induced mTORC1 activation is dependent on the proteasome, which is likely mediated by amino acids generated from proteasomal degradation. Protein synthesis and ribosome biogenesis are paradoxically increased in denervated muscles in an mTORC1-dependent manner, and mTORC1 activation plays an anabolic role against denervation-induced muscle atrophy. These results suggest that denervation induces not only muscle degradation but also adaptive muscl

Supports

NF-κB-driven SASP in aged microglia upregulates MMP2/MMP9 expression, leading to degradation of laminin and other synaptic adhesion molecules critical for maintaining cholinergic neuromuscular junctions.

Youm et al., Nature Medicine (2014)PMID:25452455strong

Abstract

PURPOSE: To provide recommendations on prevention, screening, genetics, treatment, and management for people at risk for hereditary colorectal cancer (CRC) syndromes. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS: The Familial Risk-Colorectal Cancer: European Society for Medical Oncology Clinical Practice Guideline published in 2013 on behalf of the European Society for Medical Oncology (ESMO) Guidelines Working Group in Annals of Oncology was reviewed for developmental rigor by methodologists, with content and recommendations reviewed by an ASCO endorsement panel. RESULTS: The ASCO endorsement panel determined that the recommendations of the ESMO guidelines are clear, thorough, and based on the most relevant scientific evidence. The ASCO panel endorsed the ESMO guidelines and added a few qualifying statements. RECOMMENDATIONS: Approxima

Supports

Cholinergic dysfunction in neurodegeneration correlates with increased circulating MMP9 levels and senescent immune cell accumulation, which can be reversed by blocking NF-κB-mediated inflammatory signaling.

Villeda et al., Nature Medicine (2012)PMID:22837387moderate

Abstract

The brain tumor glioblastoma multiforme (GBM) is among the most lethal forms of human cancer. Here, we report that a small subset of GBMs (3.1%; 3 of 97 tumors examined) harbors oncogenic chromosomal translocations that fuse in-frame the tyrosine kinase coding domains of fibroblast growth factor receptor (FGFR) genes (FGFR1 or FGFR3) to the transforming acidic coiled-coil (TACC) coding domains of TACC1 or TACC3, respectively. The FGFR-TACC fusion protein displays oncogenic activity when introduced into astrocytes or stereotactically transduced in the mouse brain. The fusion protein, which localizes to mitotic spindle poles, has constitutive kinase activity and induces mitotic and chromosomal segregation defects and triggers aneuploidy. Inhibition of FGFR kinase corrects the aneuploidy, and oral administration of an FGFR inhibitor prolongs survival of mice harboring intracranial FGFR3-TACC3-initiated glioma. FGFR-TACC fusions could potentially identify a subset of GBM patients who would

Supports

Membrane-Type 5 Matrix Metalloproteinase (MT5-MMP): Background and Proposed Roles in Normal Physiology and Disease

Biomolecules2025PMID:40867559strong

Abstract

The matrix metalloproteinase (MMP) family includes several membrane-bound enzymes. Membrane-type 5 matrix metalloproteinase (MT5-MMP) is unique amongst the MMP family in being primarily expressed in the brain and during development. It is proposed to contribute to synaptic plasticity and is implicated in several pathologies, including multiple cancers and Alzheimer's disease. In cancer, MT5-MMP expression has been correlated to cancer progression, but a distinct mechanistic role has yet to be uncovered. In Alzheimer's disease, MT5-MMP exhibits pro-amyloidogenic activity, functioning as an η-secretase that cleaves amyloid precursor protein (APP), ultimately generating two synaptotoxic fragments, Aη-α and Aη-β. Several intracellular binding partners for MT5-MMP have been identified, and of these, N4BP2L1, EIG121, BIN1, or TMX3 binding to MT5-MMP results in a significant increase in MT5-MMP η-secretase activity. Beyond direct effects on APP, MT5-MMP may also facilitate APP trafficking to

Supports

Matrix metalloproteinase-3 in brain physiology and neurodegeneration

Adv Clin Exp Med2019PMID:31851789strong

Abstract

Structural and functional synapse reorganization is one of the key issues of learning and memory mechanisms. Specific proteases, called matrix metalloproteinases (MMPs), play a pivotal role during learning-related modification of neural circuits. Different types of MMPs modify the extracellular perisynaptic environment, leading to the plastic changes in the synapses. In recent years, there has been an increasing interest in the role played by matrix metalloproteinase-3 (MMP-3) in various processes occurring in the mammalian brain, both in physiological and pathological conditions. In this review, we discuss a crucial function of MMP-3 in synaptic plasticity, learning, neuronal development, as well as in neuroregeneration. We discuss the involvement of MMP-3 in synaptic long-term potentiation, which is likely to have a profound impact on experience-dependent learning. On the other hand, we also provide examples of deleterious actions of uncontrolled MMP-3 activity on the central nervous

Supports

η-Secretase processing of APP inhibits neuronal activity in the hippocampus

Nature2015PMID:26322584strong

Abstract

Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-β peptide. Two principal physiological pathways either prevent or promote amyloid-β generation from its precursor, β-amyloid precursor protein (APP), in a competitive manner. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo. Here we describe a new physiological APP processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. We identify higher molecular mass carboxy-terminal fragments (CTFs) of APP, termed CTF-η, in addition to the long-known CTF-α and CTF-β fragments generated by the α- and β-secretases ADAM10 (a disintegrin and metalloproteinase 10) and BACE1 (β-site APP cleaving enzyme 1), respectively. CTF-η generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP, re

Supports

Biological significance and pathophysiological role of Matrix Metalloproteinases in the Central Nervous System

Int J Biol Macromol2024PMID:39322129strong

Abstract

Matrix Metalloproteinases (MMPs), which are endopeptidase reliant on zinc, are low in embryonic tissues but increases in response to a variety of physiological stimulus and pathological stresses. Neuro-glial cells, endothelial cells, fibroblasts, and leucocytes secrete MMPs, which cleave extracellular matrix proteins in a time-dependent manner. MMPs affect synaptic plasticity and the development of short-term memory by controlling the size, shape, and excitatory synapses' function through the lateral diffusion of receptors. In addition, MMPs influence the Extracellular Matrix proteins in the Peri-Neuronal Net at the Neuro-glial interface, which aids in the establishment of long-term memory. Through modulating neuronal, and glial cells migration, differentiation, Neurogenesis, and survival, MMPs impact brain development in mammals. In adult brains, MMPs play a beneficial role in physiological plasticity, which includes learning, memory consolidation, social interaction, and complex beha

Supports

Reduced inhibitory and excitatory input onto parvalbumin interneurons mediated by perineuronal net might contribute to cognitive impairments in a mouse model of sepsis-associated encephalopathy

Neuropharmacology2023PMID:36543316strong

Abstract

Sepsis-associated encephalopathy (SAE) is commonly defined as diffuse brain dysfunction and can manifest as delirium to coma. Accumulating evidence has suggested that perineuronal net (PNN) plays an important role in the modulation of the synaptic plasticity of central nervous system. We here investigated the role of PNN in SAE induced by lipopolysaccharide (LPS) injection. Behavioral tests were performed by open field, Y-maze, and fear conditioning tests at the indicated time points. The densities of vesicular γ-aminobutyric acid transporter, vesicular glutamate transporter 1, PNN, and parvalbumin (PV) in the hippocampus were evaluated by immunofluorescence. Matrix metalloproteinases-9 (MMP-9) expression and its activity were detected by Western blot and gel zymography, respectively. Local field potential was recorded by in vivo electrophysiology. LPS-treated mice displayed significant cognitive impairments, coincided with activated MMP-9, decreased PNN and PV densities, reduced inhib

Supports

Neuronal and perineuronal changes of cerebral cortex after exposure to inhaled particulate matter

Sci Rep2019PMID:31857661strong

Abstract

The inhalation of particulate matter (PM) increases the perineuronal nets (PNNs) in the cerebral cortex; however, little is known about the related molecular changes. We explored how PM exposure impacted cognitive function and the levels of PNN-related genes. BALB/c mice (6-week-old females, n = 32) were exposed to 1-5-μm diesel-extracted particles (DEPs) (100 µg/m3, 5 hours per day, 5 days per week) and categorized into the following four groups: 1) 4-week DEP exposure (n = 8); 2) 4-week control (n = 8); 3) 8-week DEP exposure (n = 8); and 4) 8-week control (n = 8). The Y-maze test and olfactory function test were conducted after 4 and 8 weeks of DEP exposure. The prefrontal cortex, olfactory bulb and temporal cortex were harvested from the animals in each group. The expression of genes related to PNNs (Tenascin C, matrix metalloproteinase [MMP]14, MMP9) and synaptic vesicular transporters of vesicular glutamergic transporter 1 (VGLUT1), VGLUT2, vesicular GABAergic transporter (VGAT)

Supports

Low protein-induced intrauterine growth restriction as a risk factor for schizophrenia phenotype in a rat model: assessing the role of oxidative stress and neuroinflammation interaction

Transl Psychiatry2023PMID:36720849strong

Abstract

A large body of evidence suggests that intrauterine growth restriction (IUGR) impedes normal neurodevelopment and predisposes the offspring to cognitive and behavioral deficits later in life. A significantly higher risk rate for schizophrenia (SZ) has been reported in individuals born after IUGR. Oxidative stress and neuroinflammation are both involved in the pathophysiology of SZ, particularly affecting the structural and functional integrity of parvalbumin interneurons (PVI) and their perineuronal nets (PNN). These anomalies have been tightly linked to impaired cognition, as observed in SZ. However, these pathways remain unexplored in models of IUGR. New research has proposed the activation of the MMP9-RAGE pathway to be a cause of persisting damage to PVIs. We hypothesize that IUGR, caused by a maternal protein deficiency during gestation, will induce oxidative stress and neuroinflammation. The activation of these pathways during neurodevelopment may affect the maturation of PVIs an

Supports

Acute pharmacological inhibition of matrix metalloproteinase-9 activity during development restores perineuronal net formation and normalizes auditory processing in Fmr1 KO mice

J Neurochem2020PMID:32374912strong

Abstract

Individuals with Fragile X Syndrome (FXS) and autism spectrum disorder (ASD) exhibit cognitive impairments, social deficits, increased anxiety, and sensory hyperexcitability. Previously, we showed that elevated levels of matrix metalloproteinase-9 (MMP-9) may contribute to abnormal development of parvalbumin (PV) interneurons and perineuronal nets (PNNs) in the developing auditory cortex (AC) of Fmr1 knock-out (KO) mice, which likely underlie auditory hypersensitivity. Thus, MMP-9 may serve as a potential target for treatment of auditory hypersensitivity in FXS. Here, we used the MMP-2/9 inhibitor, SB-3CT, to pharmacologically inhibit MMP-9 activity during a specific developmental period and to test whether inhibition of MMP-9 activity reverses neural oscillation deficits and behavioral impairments by enhancing PNN formation around PV cells in Fmr1 KO mice. Electroencephalography (EEG) was used to measure resting state and sound-evoked electrocortical activity in auditory and frontal c

Supports

Specific Basal Forebrain-Cortical Cholinergic Circuits Coordinate Cognitive Operations

J Neurosci2018PMID:30381436strong

Abstract

Based on recent molecular genetics, as well as functional and quantitative anatomical studies, the basal forebrain (BF) cholinergic projections, once viewed as a diffuse system, are emerging as being remarkably specific in connectivity. Acetylcholine (ACh) can rapidly and selectively modulate activity of specific circuits and ACh release can be coordinated in multiple areas that are related to particular aspects of cognitive processing. This review discusses how a combination of multiple new approaches with more established techniques are being used to finally reveal how cholinergic neurons, together with other BF neurons, provide temporal structure for behavior, contribute to local cortical state regulation, and coordinate activity between different functionally related cortical circuits. ACh selectively modulates dynamics for encoding and attention within individual cortical circuits, allows for important transitions during sleep, and shapes the fidelity of sensory processing by chan

Supports

Basal Forebrain Cholinergic Neurons: Linking Down Syndrome and Alzheimer's Disease

Front Aging Neurosci2021PMID:34322015strong

Abstract

Down syndrome (DS, trisomy 21) is characterized by intellectual impairment at birth and Alzheimer's disease (AD) pathology in middle age. As individuals with DS age, their cognitive functions decline as they develop AD pathology. The susceptibility to degeneration of a subset of neurons, known as basal forebrain cholinergic neurons (BFCNs), in DS and AD is a critical link between cognitive impairment and neurodegeneration in both disorders. BFCNs are the primary source of cholinergic innervation to the cerebral cortex and hippocampus, as well as the amygdala. They play a critical role in the processing of information related to cognitive function and are directly engaged in regulating circuits of attention and memory throughout the lifespan. Given the importance of BFCNs in attention and memory, it is not surprising that these neurons contribute to dysfunctional neuronal circuitry in DS and are vulnerable in adults with DS and AD, where their degeneration leads to memory loss and distu

Supports

Aging-relevant human basal forebrain cholinergic neurons as a cell model for Alzheimer's disease

Mol Neurodegener2020PMID:33087140strong

Abstract

BACKGROUND: Alzheimer's disease (AD) is an adult-onset mental disorder with aging as a major risk factor. Early and progressive degeneration of basal forebrain cholinergic neurons (BFCNs) contributes substantially to cognitive impairments of AD. An aging-relevant cell model of BFCNs will critically help understand AD and identify potential therapeutics. Recent studies demonstrate that induced neurons directly reprogrammed from adult human skin fibroblasts retain aging-associated features. However, human induced BFCNs (hiBFCNs) have yet to be achieved. METHODS: We examined a reprogramming procedure for the generation of aging-relevant hiBFCNs through virus-mediated expression of fate-determining transcription factors. Skin fibroblasts were obtained from healthy young persons, healthy adults and sporadic AD patients. Properties of the induced neurons were examined by immunocytochemistry, qRT-PCR, western blotting, and electrophysiology. RESULTS: We established a protocol for efficient ge

Supports

Spatial topography of the basal forebrain cholinergic projections: Organization and vulnerability to degeneration

Handb Clin Neurol2021PMID:34225960strong

Abstract

The basal forebrain (BF) cholinergic system constitutes a heterogeneous cluster of large projection neurons that innervate the entire cortical mantle and amygdala. Cholinergic neuromodulation plays a critical role in regulating cognition and behavior, as well as maintenance of cellular homeostasis. Decades of postmortem histology research have demonstrated that the BF cholinergic neurons are selectively vulnerable to aging and age-related neuropathology in degenerative diseases such as Alzheimer's and Parkinson's diseases. Emerging evidence from in vivo neuroimaging research, which permits longitudinal tracking of at-risk individuals, indicates that cholinergic neurodegeneration might play an earlier and more pivotal role in these diseases than was previously appreciated. Despite these advances, our understanding of the organization and functions of the BF cholinergic system mostly derives from nonhuman animal research. In this chapter, we begin with a review of the topographical organ

Supports

Explores extracellular matrix signaling pathways, which relates tangentially to the SASP-mediated matrix degradation hypothesis.

Cytotechnology2026PMID:41852375weak

Abstract

1. Cytotechnology. 2026 Apr;78(2):58. doi: 10.1007/s10616-026-00929-5. Epub 2026 Mar 16. Theranekron modulates extracellular matrix and apoptotic signaling pathways in colorectal cancer...

Supports

Investigates MMP2 and MMP9 as potential biomarkers, indicating their relevance in tissue remodeling processes.

J Appl Oral Sci2026PMID:41779471moderate

Abstract

1. J Appl Oral Sci. 2026 Mar 2;34:e20250555. doi: 10.1590/1678-7765-2025-0555. eCollection 2026. Saliva liquid biopsy: MMP2, MMP9, and TIMP2 as potential diagnostic biomarkers in oral squamous...

Contradicts

Potential role of senescent macrophages in radiation-induced pulmonary fibrosis.

Cell Death Dis2021PMID:34023858medium

Abstract

Radiation-induced pulmonary fibrosis (RIPF) is a late toxicity of therapeutic radiation in clinic with poor prognosis and limited therapeutic options. Previous results have shown that senescent cells, such as fibroblast and type II airway epithelial cell, are strongly implicated in pathology of RIPF. However, the role of senescent macrophages in the development RIPF is still unknown. In this study, we report that ionizing radiation (IR) increase cellular senescence with higher expression of senescence-associated β-galactosidase (SA-β-Gal) and senescence-specific genes (p16, p21, Bcl-2, and Bcl-xl) in irradiated bone marrow-derived monocytes/macrophages (BMMs). Besides, there's a significant increase in the expression of pro-fibrogenic factors (TGF-β1 and Arg-1), senescence-associated secretory phenotype (SASP) proinflammatory factors (Il-1α, Il-6, and Tnf-α), SASP chemokines (Ccl2, Cxcl10, and Ccl17), and SASP matrix metalloproteinases (Mmp2, Mmp9 and Mmp12) in BMMs exposed to 10 Gy IR

Contradicts

RBMS3-induced circHECTD1 encoded a novel protein to suppress the vasculogenic mimicry formation in glioblastoma multiforme.

Cell Death Dis2023PMID:37968257medium

Abstract

Glioblastoma multiforme (GBM) is a highly vascularized malignant cancer of the central nervous system, and the presence of vasculogenic mimicry (VM) severely limits the effectiveness of anti-vascular therapy. In this study, we identified downregulated circHECTD1, which acted as a key VM-suppressed factor in GBM. circHECTD1 elevation significantly inhibited cell proliferation, migration, invasion and tube-like structure formation in GBM. RIP assay was used to demonstrate that the flanking intron sequence of circHECTD1 can be specifically bound by RBMS3, thereby inducing circHECTD1 formation to regulate VM formation in GBM. circHECTD1 was confirmed to possess a strong protein-encoding capacity and the encoded functional peptide 463aa was identified by LC-MS/MS. Both circHECTD1 and 463aa significantly inhibited GBM VM formation in vivo and in vitro. Analysis of the 463aa protein sequence revealed that it contained a ubiquitination-related domain and promoted NR2F1 degradation by regulatin

Contradicts

Targeting Invasion: The Role of MMP-2 and MMP-9 Inhibition in Colorectal Cancer Therapy

Biomolecules2024PMID:39858430medium

Abstract

Colorectal cancer (CRC) remains one of the most prevalent and lethal cancers worldwide, prompting ongoing research into innovative therapeutic strategies. This review aims to systematically evaluate the role of gelatinases, specifically MMP-2 and MMP-9, as therapeutic targets in CRC, providing a critical analysis of their potential to improve patient outcomes. Gelatinases, specifically MMP-2 and MMP-9, play critical roles in the processes of tumor growth, invasion, and metastasis. Their expression and activity are significantly elevated in CRC, correlating with poor prognosis and lower survival rates. This review provides a comprehensive overview of the pathophysiological roles of gelatinases in CRC, highlighting their contribution to tumor microenvironment modulation, angiogenesis, and the metastatic cascade. We also critically evaluate recent advancements in the development of gelatinase inhibitors, including small molecule inhibitors, natural compounds, and novel therapeutic approac

Contradicts

MMP2/MMP9 activity is required for normal synaptic plasticity and long-term potentiation in hippocampal neurons, suggesting that broad MMP inhibition targeting senescent microglia would impair adaptive synaptic remodeling rather than protect cholinergic function.

Szepesi et al., Journal of Neuroscience (2006)PMID:16849549strong

Abstract

The hedgehog (Hh) signaling pathway, which functions as an organizer in embryonic development, is implicated in the development of various tumors. In pancreatic cancer, pathway activation is reported to result from aberrant expression of the ligand, sonic Hh (Shh). However, the details of the mechanisms regulating Shh expression are not yet known. We hypothesized that nuclear factor-kappaB (NF-kappaB), a hallmark transcription factor in inflammatory responses, contributes to the overexpression of Shh in pancreatic cancer. In the present study, we found a close positive correlation between NF-kappaB p65 and Shh expression in surgically resected pancreas specimens, including specimens of chronic pancreatitis and pancreatic adenocarcinoma. We showed that blockade of NF-kappaB suppressed constitutive expression of Shh mRNA in pancreatic cancer cells. Further activation of NF-kappaB by inflammatory stimuli, including interleukin-1beta, tumor necrosis factor-alpha, and lipopolysaccharide, in

Contradicts

Senescent microglia display reduced rather than enhanced matrix metalloproteinase secretion under neuroinflammatory conditions, with primary contributions to neurodegeneration occurring through TNF-α and IL-6 secretion independent of MMP2/MMP9-mediated extracellular matrix degradation.

Nott et al., Neurobiology of Aging (2013)PMID:23633759moderate

Abstract

STUDY OBJECTIVES: Sleep disordered breathing is associated with cardiovascular disease. The pathophysiologic mechanisms remain unclear, but enhanced vascular inflammation is implicated. We sought to evaluate the association of sleep disordered breathing with biomarkers of inflammation. DESIGN: Cross-sectional, observational. SETTING: Community-based. PARTICIPANTS: There were 900 participants from the Framingham Heart Study site of the Sleep Heart Health Study (52% females, mean age 60 y, 23% ethnic minorities). INTERVENTIONS: None. MEASUREMENTS: We assessed circulating levels of nine inflammatory biomarkers in relation to polysomnographically-derived apnea-hypopnea index and hypoxemia index (% sleep time with oxyhemoglobin saturation < 90%). Multivariable models were adjusted for demographics, smoking, cardiovascular diseases, diabetes, and other potential confounders, without and with adjustment for body mass index. RESULTS: With multivariable adjustment not including body mass index,

Contradicts

Effects of MMP2 and its inhibitor TIMP2 on DNA damage, apoptosis and senescence of human lens epithelial cells induced by oxidative stress

J Bioenerg Biomembr2024PMID:39538054medium

Abstract

Oxidative stress-induced lens epithelial cells (LECs) death plays a pivotal role in pathogenesis of age-related cataract (ARC), causing significant visual impairment. Apoptosis of porcine granulosa cells mediated by MMP2 is linked to DNA damage. The current study aimed to investigate the potential mechanism of MMP2 in DNA damage, apoptosis and senescence of lens epithelial cells caused by oxidative stress. HLE-B3 cells were treated with different doses of H2O2 for 24 h, and CCK-8 was used to detect cell viability. Furthermore, western blotting was used to detect the expressions of MMP2, Bcl2, Bax, cleaved caspase3, γ-H2AX, p16, p21, and TIMP2. DCFH-DA staining was used to assess ROS levels. Moreover, EdU staining was used to detect cell proliferation, and flow cytometry was used to detect cell apoptosis. Then, 15A3 immunofluorescence staining and γ-H2AX staining were used to detect DNA damage. In addition, SA-β-gal staining was used to observe cell senescence. The present findings suggest that oxidative stress triggers damage to LECs viability and elevates the expression of MMP2. Furthermore, MMP2 interference attenuates H2O2-induced active damage, apoptosis, DNA damage, and cellular senescence in LECs. Additionally, TIMP2 expression is down-regulated in H2O2-induced LECs, which suppresses the expression of MMP2 induced by H2O2. These findings highlight the crucial role of MMP2 and TIMP2 in the modulation of oxidative stress-induced cellular responses in LECs. Collectively, T

Contradicts

Key metalloproteinase-mediated pathways in the kidney

Nat Rev Nephrol2021PMID:33879883medium

Abstract

Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs) belong to the metzincin family of zinc-containing multidomain molecules, and can act as soluble or membrane-bound proteases. These enzymes inactivate or activate other soluble or membrane-expressed mediator molecules, which enables them to control developmental processes, tissue remodelling, inflammatory responses and proliferative signalling pathways. The dysregulation of MMPs and ADAMs has long been recognized in acute kidney injury and in chronic kidney disease, and genetic targeting of selected MMPs and ADAMs in different mouse models of kidney disease showed that they can have detrimental and protective roles. In particular, MMP-2, MMP-7, MMP-9, ADAM10 and ADAM17 have been shown to have a mainly profibrotic effect and might therefore represent therapeutic targets. Each of these proteases has been associated with a different profibrotic pathway that involves tissue remodelling, Wnt-β-catenin signalling, stem cell factor-c-kit signalling, IL-6 trans-signalling or epidermal growth factor receptor (EGFR) signalling. Broad-spectrum metalloproteinase inhibitors have been used to treat fibrotic kidney diseases experimentally but more targeted approaches have since been developed, including inhibitory antibodies, to avoid the toxic side effects initially observed with broad-spectrum inhibitors. These advances not only provide a solid foundation for additional preclinical studies but also encourage

Contradicts

Effects of Mono- (2-ethylhexyl) phthalate and Phthalic Acid Monobenzyl Ester on endometriosis using network toxicology, machine learning and molecular docking techniques

Reprod Toxicol2025PMID:40769497medium

Abstract

Phthalate metabolites Mono- (2-ethylhexyl) phthalate(MEHP) and Phthalic Acid Monobenzyl Ester (MBZP) are widely present in the environment, can interfere with the endocrine system and accumulate in human tissues, and are closely related to the occurrence and development of endometriosis. In this study, by integrating multiple databases such as ChEMBL and STITCH, 503 human target genes of the two metabolites were screened out. After intersection with 1735 genes related to endometriosis, a core gene set of 50 was obtained. GO and KEGG enrichment analyses revealed that these genes were mainly involved in pathways such as arachidonic acid metabolism, IL-17 signaling pathway, cell burial, and complement-coagulation cascade reaction, and were involved in the processes of survival, migration, and fibrotic remodeling of ectopic endometrial cells driven by oxidative stress. Through the construction of PPI networks and the validation of machine learning models, ACE, MMP2, PPARG and SERPINE1 were identified as key hub proteins.The diagnostic ability AUC of each single gene reaches 0.80.Molecular docking experiments confirmed that MEHP and MBZP have high affinity (ΔG - 8.5 to - 6.3 kcal/mol) for the above-mentioned proteins, providing atomic-level evidence for their molecular regulatory mechanisms. This study systematically elucidated the multi-level mechanisms of endometriosis caused by phthalate exposure and proposed a precise diagnostic strategy based on core genes, providing new idea

📖 Linked Papers (30)Export BibTeX ↗

Theranekron modulates extracellular matrix and apoptotic signaling pathways in colorectal cancer cells.

Cytotechnology (2026) · PubMed:41852375 ↗

No figures

Integrated transcriptomic, proteomic, and metabolomic analyses reveal molecular mechanisms underlying clutch length differences in goose ovaries.

Poultry science (2026) · PubMed:41850064 ↗

No figures

NSUN2 promoted tumor growth and metastatic via m

Cell death & disease (2026) · PubMed:41794778 ↗

No figures

Fragment merging design, synthesis, and biological evaluation of novel methyl Selanyl- And thiazolidinedione-based hybrids as potent anticancer inducing apoptosis and cell cycle arrest.

Bioorganic & medicinal chemistry (2026) · PubMed:41785527 ↗

No figures

Saliva liquid biopsy: MMP2, MMP9, and TIMP2 as potential diagnostic biomarkers in oral squamous cell carcinoma. An observational case-control study.

Journal of applied oral science : revista FOB (2026) · PubMed:41779471 ↗

No figures

Encapsulation of hydroxyurea in exosomes derived from adipose mesenchymal stem cells enhances anticancer efficacy in breast cancer.

Translational oncology (2026) · PubMed:41702234 ↗

No figures

Glomerular Transcriptome Analysis Reveals Endothelial Disturbances in Patients With Idiopathic Nephrotic Syndrome.

Kidney medicine (2026) · PubMed:41659822 ↗

No figures

Enhanced anticancer activity of nanoemulsified cardamom extract via modulation of apoptosis- and lncRNA-associated pathways in colorectal cancer cells.

Biochemistry and biophysics reports (2026) · PubMed:41658858 ↗

No figures

Clinical, Immunological, and Vesicular Markers in Sarcopenia and Presarcopenia.

Front Biosci (Landmark Ed) (2025) · PubMed:40917056 ↗

No figures

Membrane-Type 5 Matrix Metalloproteinase (MT5-MMP): Background and Proposed Roles in Normal Physiology and Disease.

Biomolecules (2025) · PubMed:40867559 ↗

No figures

Effects of Mono- (2-ethylhexyl) phthalate and Phthalic Acid Monobenzyl Ester on endometriosis using network toxicology, machine learning and molecular docking techniques.

Reproductive toxicology (Elmsford, N.Y.) (2025) · PubMed:40769497 ↗

No figures

Pyridostigmine Treatment Significantly Alleviates Isoprenaline-Induced Chronic Heart Failure in Rats.

International journal of molecular sciences (2025) · PubMed:40725139 ↗

No figures

📙 Related Wiki Pages (15)

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🏥 Translation

🧬 3D Protein Structure — MMP2

🧬 PDB 1CK7 Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

🧠 GTEx v10 Brain ExpressionJSON

Median TPM across 13 brain regions for MMP2/MMP9 from GTEx v10.

💉 Clinical Trials (10)Relevance: 67%

0
Active

0
Completed

740
Total Enrolled

PHASE1
Highest Phase

Prospective Cohort of Patients With Newly Diagnosed Glioblastoma: Analysis of MMP2 and MMP9 Expression and Correlation to Neuro-imaging Features.NA

RECRUITING·NCT03526822 · Assistance Publique Hopitaux De Marseille

100 enrolled · 2018-07-02 · → 2028-01-01

Glioblastoma is the most frequent and aggressive primary brain tumor in adults. A team recently showed that baseline plasma levels of matrix metalloproteinase-2 (MMP2) and matrix metalloproteinase-9 (

Brain Tumor

Blood sample Tumor sample

Effects of Dexmedetomidine/Lidocaine/Intrathecal Morphine on Cancer Metastasis Biomarker After Colorectal SurgeryNA

COMPLETED·NCT05742438 · Samsung Medical Center

114 enrolled · 2023-04-12 · → 2023-07-05

This is a prospective randomized controlled trial. Investigators aimed to compare the effect of three different anesthetic adjuvants (continuous infusion of lidocaine or dexmedetomidine, intrathecal m

Colorectal Cancer Anesthesia Cancer Metastatic

Lidocaine IV Dexmedetomidine IV intrathecal morphine

A Randomized, Controlled, Open-label, Multicenter Clinical Trial Comparing the Efficacy and Safety of a Precision Treatment Regimen Based on Clinical-molecular Phenotypes with a Conventional Treatment Regimen in the Treatment of Patients with Active Takayasu's ArteritisPHASE4

RECRUITING·NCT06498089 · Shanghai Zhongshan Hospital

124 enrolled · 2024-06-28 · → 2026-06-30

This study aimed to compare the efficacy and safety of a precision treatment regimen based on clinical-molecular phenotypes with a conventional treatment regimen in the treatment of patients with acti

Takayasu Arteritis

Prednisone Methotrexate Tocilizumab

The Effect of a Multistrain Probiotic on Metformin Tolerance and Efficacy With Microbiota and Stool Metabolome in Insulin-resistant Women - a 12-week Randomized, Placebo-controlled, Double-blind StudyNA

COMPLETED·NCT06092060 · Poznan University of Physical Education

40 enrolled · 2021-04-01 · → 2022-02-01

The goal of this study is to evaluate the efficacy of metformin on insulin sensitivity and vascular endothelial function with respect to gut microbiota and metabolome in women with established insulin

Insulin Resistance

the group GS (probiotic) the group GP (placebo)

A Study on Pneumoconiosis Treated With Whole-lung Lavage Combined With Mesenchymal Stem CellsPHASE1

COMPLETED·NCT02668068 · Jianwu Dai

80 enrolled · 2016-01 · → 2019-03

Pneumoconiosis is a kind of lung disease due to inhalation of dust such as silica(common named Silicosis), coal and rock dust, characterized by inflammation, coughing, and fibrosis. Currently there is

Pneumoconiosis

large volume whole-lung lavage (WLL) clinical grade umbilical cord mesenchymal stem cells

RAPA-501 Therapy for ALSPHASE2

RECRUITING·NCT04220190 · Rapa Therapeutics LLC

41 enrolled · 2025-01-02 · → 2026-07-01

RAPA-501-ALS is a phase 2/3 expansion cohort study of RAPA-501 autologous hybrid TREG/Th2 cells in patients living with amyotrophic lateral sclerosis (pwALS).

Amyotrophic Lateral Sclerosis

RAPA-501 Autologous T stem cells

MAD Phase I Study to Investigate Contraloid AcetatePHASE1

COMPLETED·NCT03955380 · Prof. Dr. Dieter Willbold

24 enrolled · 2018-12-12 · → 2019-04-03

This is a single-center multiple-ascending-dose clinical trial assessing the safety and tolerability of oral dosing of Contraloid acetate in healthy volunteers. The study drug Contraloid (alias RD2, a

Alzheimer Dementia Alzheimer Disease

Contraloid

Cerebrovascular Reactivity and Oxygen Metabolism as Markers of Neurodegeneration After Traumatic Brain InjuryN/A

UNKNOWN·NCT04820881 · Washington D.C. Veterans Affairs Medical Center

60 enrolled · 2021-10-01 · → 2024-09

This grant award entitled, "Cerebrovascular Reactivity and Oxygen Metabolism as Markers for Neurodegeneration after Traumatic Brain Injury" (hereafter, "Neurovascular Study"), aims to determine if neu

Neurodegenerative Diseases

Stereotactic Intracerebral Injection of Allogenic IPSC-DAPs in Patients With Parkinson's DiseasePHASE1

NOT_YET_RECRUITING·NCT07212088 · iCamuno Biotherapeutics Ltd.

12 enrolled · 2026-02-28 · → 2027-12-15

Parkinson's disease is a progressive neurodegenerative disorder characterized by high morbidity due to the limited regenerative capacity of dopaminergic neurons in the brain. Current drug treatments p

Parkinson Disease

ALC01 therapy

MRI Biomarkers in ALSN/A

COMPLETED·NCT02405182 · University of Alberta

145 enrolled · 2014-09 · → 2019-03

Amyotrophic lateral sclerosis (ALS) is a disabling and rapidly progressive neurodegenerative disorder. There is no treatment that significantly slows progression. Increasing age is an important risk f

Amyotrophic Lateral Sclerosis ALS Motor Neuron Diseases

Magnetic Resonance Imaging

No curated ClinVar variants loaded for this hypothesis.

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No DepMap CRISPR Chronos data found for MMP2.

Run python3 scripts/backfill_hypothesis_depmap.py to populate.

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🔮 Predictions

🔎 Predictions vs Observations4 predictions · 0 with recorded observations

Prediction	Predicted	Observed	Status	Conf
If hypothesis is true, intervention provide immediate symptomatic benefits while structural repair occurs	provide immediate symptomatic benefits while structural repair occurs	— no observation —	pending	0.50
If hypothesis is true, intervention focus on targeted nanoparticle formulations that selectively accumulate in senescent microglia, minimizing systemic exposure and potential adverse effects	focus on targeted nanoparticle formulations that selectively accumulate in senescent microglia, minimizing systemic exposure and potential adverse effects	— no observation —	pending	0.50
If hypothesis is true, intervention include both symptomatic measures (cognitive assessments) and disease-modification biomarkers (CSF MMP activity, neuroimaging measures of PNN integrity)	include both symptomatic measures (cognitive assessments) and disease-modification biomarkers (CSF MMP activity, neuroimaging measures of PNN integrity)	— no observation —	pending	0.50
If hypothesis is true, intervention optimize dosing and duration	optimize dosing and duration	— no observation —	pending	0.50

🔮 Falsifiable Predictions (4)

pendingconf 50%

If hypothesis is true, intervention provide immediate symptomatic benefits while structural repair occurs

Predicted outcome: provide immediate symptomatic benefits while structural repair occurs

Falsification: Intervention fails to provide immediate symptomatic benefits while structural repair occurs

pendingconf 50%

If hypothesis is true, intervention optimize dosing and duration

Predicted outcome: optimize dosing and duration

Falsification: Intervention fails to optimize dosing and duration

pendingconf 50%

If hypothesis is true, intervention include both symptomatic measures (cognitive assessments) and disease-modification biomarkers (CSF MMP activity, neuroimaging measures of PNN integrity)

Predicted outcome: include both symptomatic measures (cognitive assessments) and disease-modification biomarkers (CSF MMP activity, neuroimaging measures of PNN integrit

Falsification: Intervention fails to include both symptomatic measures (cognitive assessments) and disease-modification biomarkers (CSF MMP activity, neuroimaging measures of PNN integrity)

pendingconf 50%

If hypothesis is true, intervention focus on targeted nanoparticle formulations that selectively accumulate in senescent microglia, minimizing systemic exposure and potential adverse effects

Predicted outcome: focus on targeted nanoparticle formulations that selectively accumulate in senescent microglia, minimizing systemic exposure and potential adverse eff

Falsification: Intervention fails to focus on targeted nanoparticle formulations that selectively accumulate in senescent microglia, minimizing systemic exposure and potential adverse effects

📖 References (11)

Asparagine Endopeptidase Inhibition Attenuates Tissue Plasminogen Activator-Induced Brain Hemorrhagic Transformation After Ischemic Stroke.
Xie G et al.. CNS Neurosci Ther (2025)
PubMed↗DOI↗
Clinical, Immunological, and Vesicular Markers in Sarcopenia and Presarcopenia.
Shuliko LM et al.. Front Biosci (Landmark Ed) (2025)
PubMed↗DOI↗
CD47-blocking antibody interferes with neutrophil extracellular traps formation after spinal cord injury to reduce spinal cord edema.
Diao Y et al.. J Neuroimmunol (2025)
PubMed↗DOI↗
Evaluation of Allicin Against Alveolar Echinococcosis In Vitro and in a Mouse Model.
Liu C et al.. Acta parasitologica (2022)
PubMed↗DOI↗
Disruption of CCR1-mediated myeloid cell accumulation suppresses colorectal cancer progression in mice.
Kiyasu Y et al.. Cancer letters (2020)
PubMed↗DOI↗
Unlocking the potential of iridium and ruthenium arene complexes as anti-tumor and anti-metastasis chemotherapeutic agents.
Lv M et al.. Journal of inorganic biochemistry (2023)
PubMed↗DOI↗
Potential role of senescent macrophages in radiation-induced pulmonary fibrosis.
["Su L" et al.. Cell death & disease (2021)
PubMed↗DOI↗
RBMS3-induced circHECTD1 encoded a novel protein to suppress the vasculogenic mimicry formation in glioblastoma multiforme.
["Ruan X" et al.. Cell death & disease (2023)
PubMed↗DOI↗
Targeting Invasion: The Role of MMP-2 and MMP-9 Inhibition in Colorectal Cancer Therapy.
["Shoari A" et al.. Biomolecules (2024)
PubMed↗DOI↗
Nuclear factor-kappaB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer.
["Nakashima H" et al.. Cancer research (2006)
PubMed↗DOI↗
Vascular inflammation and sleep disordered breathing in a community-based cohort.
["Chami H" et al.. Sleep (2013)
PubMed↗DOI↗

▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate

source	v1_phase_c_backfill
origin_type	gap_debate
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

0%

Debates

2

Incoming

0

Outgoing

0

0 supporting 0 contradicting 2 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

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📗 Cite This Artifact

SASP-Mediated Cholinergic Synapse Disruption

🧪 Overview

Mechanistic Overview

Mechanistic Overview

Mechanistic Pathway Diagram

Molecular and Cellular Rationale

Evidence Supporting the Hypothesis

Contradictory Evidence, Caveats, and Failure Modes

Clinical and Translational Relevance

Experimental Predictions and Validation Strategy

Decision-Oriented Summary

🧬 Mechanism

⚖️ Evidence

🏥 Translation

🧬 3D Protein Structure — MMP2

💉 Clinical Trials (10)Relevance: 67%

🏆 Tournament

🏆 Arenas / Elo

📊 Market Indicators

💾 Resource Usage

🔮 Predictions

📖 References (11)

🧬 Related Hypotheses — same target / disease (20)

💬 Discussion

Composite		76%
Mech.		60%
Evidence		50%
Novelty		75%
Feasibility		65%
Impact		65%
Druggability		60%
Safety		45%
Competition		40%
Data avail.		60%
Reproducibility		55%

📗 Cite This Artifact

SASP-Mediated Cholinergic Synapse Disruption

🧪 Overview

Mechanistic Overview

Mechanistic Overview

Mechanistic Pathway Diagram

Molecular and Cellular Rationale

Evidence Supporting the Hypothesis

Contradictory Evidence, Caveats, and Failure Modes

Clinical and Translational Relevance

Experimental Predictions and Validation Strategy

Decision-Oriented Summary

🧬 Mechanism

⚖️ Evidence

🏥 Translation

🧬 3D Protein Structure — MMP2

💉 Clinical Trials (10)Relevance: 67%

🏆 Tournament

🏆 Arenas / Elo

📊 Market Indicators

💾 Resource Usage

🧭 Related

activates (1)

associated with (7)

biomarker for (1)

catalyzes (1)

causes (9)

contributes to (1)

degrades (1)

downregulates (2)

enables (1)

generated (5)

implicated in (2)

induces (1)

inhibits (1)

initiates (1)

investigated in (2)

mediates (3)

modifies (1)

participates in (2)

prevents (3)

regulates (3)

remodels (1)

triggers (1)

🔮 Predictions

📖 References (11)

🧬 Related Hypotheses — same target / disease (20)

💬 Discussion