Senescence-Activated NAD+ Depletion Rescue

Target: CD38/NAMPT Composite Score: 0.755 Price: $0.77▲29.9% Citation Quality: Pending neurodegeneration Status: promoted

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

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B+

Composite: 0.755

Top 13% of 1222 hypotheses

T1 Established

Multi-source converged and validated

T0 Axiom requires manual override only

B Mech. Plausibility 15% 0.65 Top 51%

B Evidence Strength 15% 0.60 Top 47%

B+ Novelty 12% 0.75 Top 38%

B+ Feasibility 12% 0.70 Top 32%

B+ Impact 12% 0.75 Top 33%

A+ Druggability 10% 0.90 Top 15%

B Safety Profile 8% 0.65 Top 30%

B+ Competition 6% 0.70 Top 41%

A Data Availability 5% 0.80 Top 19%

B+ Reproducibility 5% 0.75 Top 21%

Evidence

13 supporting | 10 opposing

Citation quality: 100%

Debates

2 sessions A+

Avg quality: 0.92

Convergence

1.00 A+ 30 related hypothesis share this target

From Analysis:

Senolytic therapy for age-related neurodegeneration

Senolytics targeting p16/p21+ senescent astrocytes and microglia may reduce SASP-driven neuroinflammation.

→ View full analysis & debate transcript

Hypotheses from Same Analysis (7)

These hypotheses emerged from the same multi-agent debate that produced this hypothesis.

SASP-Mediated Complement Cascade Amplification

Score: 0.910 | Target: C1Q/C3

SASP-Driven Microglial Metabolic Reprogramming in Synaptic Phagocytosis

Score: 0.796 | Target: HK2/PFKFB3

SASP-Driven Aquaporin-4 Dysregulation

Score: 0.782 | Target: AQP4

SASP-Mediated Cholinergic Synapse Disruption

Score: 0.763 | Target: MMP2/MMP9

Senescent Cell Mitochondrial DNA Release

Score: 0.742 | Target: CGAS/STING1/DNASE2

Senescence-Associated Myelin Lipid Remodeling

Score: 0.732 | Target: PLA2G6/PLA2G4A

Senescence-Induced Lipid Peroxidation Spreading

Score: 0.730 | Target: GPX4/SLC7A11

→ View full analysis & all 8 hypotheses

Description

Mechanistic Overview

...

Mechanistic Overview

Senescence-Activated NAD+ Depletion Rescue starts from the claim that modulating CD38/NAMPT within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "Molecular Mechanism and Rationale The senescence-activated NAD+ depletion hypothesis centers on the enzymatic activity of CD38, a multifunctional ectoenzyme that functions as the primary NAD+ glycohydrolase in mammalian tissues. CD38 exhibits dual enzymatic activities: it catalyzes the hydrolysis of NAD+ to adenosine diphosphoribose (ADPR) and nicotinamide, while also synthesizing cyclic ADPR (cADP-ribose), a potent calcium-mobilizing second messenger. In the context of neurodegeneration, senescent glial cells—particularly microglia and astrocytes—dramatically upregulate CD38 expression as part of the senescence-associated secretory phenotype (SASP). This upregulation creates discrete microdomains of NAD+ depletion surrounding senescent cells, establishing metabolic "dead zones" that compromise the bioenergetic integrity of neighboring neurons. The molecular cascade begins when DNA damage, oxidative stress, or protein aggregates trigger cellular senescence in glial populations. Senescent cells activate p53/p21 and p16INK4a/Rb pathways, leading to cell cycle arrest and SASP activation. Within the SASP program, transcription factors including NF-κB and C/EBPβ directly upregulate CD38 expression 10-20 fold above baseline levels. The resulting CD38 overexpression creates a metabolic sink that rapidly depletes extracellular and cytosolic NAD+ pools within a 50-100 μm radius of senescent cells. The mechanistic relationship between CD38 and NAMPT creates a critical metabolic bottleneck. CD38's NADase activity operates with a Km of approximately 100 μM and Vmax values that can consume cellular NAD+ pools within minutes when highly expressed. Simultaneously, NAMPT, which catalyzes the rate-limiting step in the NAD+ salvage pathway by converting nicotinamide to nicotinamide mononucleotide (NMN), becomes overwhelmed by the massive nicotinamide release from CD38 activity. This creates a futile cycle where CD38 generates excessive nicotinamide substrate while simultaneously depleting the NAD+ cofactor pool faster than NAMPT can regenerate it. At the cellular level, NAD+ depletion triggers a cascade of metabolic dysfunction. The NAD+/NADH ratio drops below the critical threshold of 3:1 required for optimal glycolytic flux, forcing neurons into inefficient anaerobic metabolism. Mitochondrial respiration becomes severely compromised as Complex I (NADH:ubiquinone oxidoreductase) activity declines, reducing ATP synthesis by 40-60%. The resulting energy crisis activates AMP-activated protein kinase (AMPK), which attempts to restore energy homeostasis by inhibiting anabolic processes and promoting catabolism, ultimately leading to synaptic pruning and dendritic retraction. Preclinical Evidence Extensive preclinical validation supports the senescence-NAD+ depletion hypothesis across multiple model systems and neurodegenerative contexts. In the 5xFAD Alzheimer's disease mouse model, immunohistochemical analysis reveals 15-20 fold increases in CD38 expression specifically in senescent microglia and astrocytes surrounding amyloid plaques. These CD38-positive cells co-localize with p16INK4a and SA-β-galactosidase markers, confirming their senescent phenotype. Quantitative NAD+ measurements using enzymatic cycling assays demonstrate 50-70% reductions in tissue NAD+ levels within 100 μm of senescent cell clusters, correlating directly with neuronal dysfunction markers including reduced mitochondrial membrane potential and decreased synaptic protein expression. Pharmacological validation in APP/PS1 mice using the CD38 inhibitor 78c demonstrates rescue of NAD+ depletion and cognitive improvement. Chronic treatment with 78c (10 mg/kg daily for 12 weeks) restores tissue NAD+ levels to 85% of wild-type controls and reduces senescent cell burden by 45%. Behavioral assessment using the Morris water maze reveals significant improvement in spatial learning (platform finding time reduced from 45±8 seconds to 28±5 seconds) and memory retention (probe trial quadrant preference increased from 28% to 42%). Complementary genetic evidence comes from CD38 knockout studies in multiple neurodegenerative models. CD38-/- mice crossed with 5xFAD backgrounds show dramatically preserved cognitive function despite similar amyloid plaque burden. Transcriptomic analysis reveals maintained expression of synaptic plasticity genes including Arc, Egr1, and Fos, while wild-type 5xFAD mice show 60-80% downregulation of these immediate early genes. Proteomic studies confirm preserved postsynaptic density proteins (PSD-95, NMDAR subunits, AMPAR subunits) in CD38-deficient mice. In vitro validation using human iPSC-derived neurons co-cultured with senescent astrocytes recapitulates the key pathological features. Senescent astrocytes, induced by treatment with bleomycin or hydrogen peroxide, upregulate CD38 expression 12-fold and create zones of NAD+ depletion extending 80-120 μm from the senescent cell body. Neurons within these depletion zones show 40-60% reduced NAD+ levels, decreased mitochondrial respiration (60% reduction in oxygen consumption rate), and increased vulnerability to excitotoxic stress. Treatment with NMN (500 μM) or the NAMPT activator P7C3-A20 (1 μM) rescues neuronal NAD+ levels and restores mitochondrial function to 90% of control values. C. elegans studies provide mechanistic insights into the evolutionary conservation of this pathway. Overexpression of the CD38 ortholog in cholinergic neurons leads to progressive paralysis, reduced lifespan, and neurodegeneration markers. Conversely, genetic enhancement of NAMPT activity through the pnc-1 gene rescues neurodegeneration phenotypes even in models of protein aggregation (polyglutamine expansion or tau overexpression). Therapeutic Strategy and Delivery The therapeutic approach targets both arms of the NAD+ depletion mechanism through dual-modality intervention combining CD38 inhibition with NAMPT activation. The lead compound is a brain-penetrant small molecule cocktail consisting of 78c (a selective CD38 inhibitor) and P7C3-A20 (a NAMPT activator), formulated as nanoparticle conjugates for enhanced blood-brain barrier penetration and targeted delivery to senescent cells. The CD38 inhibitor component, 78c, is a thiazoloquin(az)olin(on)e derivative with high selectivity for CD38 (IC50 = 15 nM) over related enzymes including CD157 and ARTCs. Medicinal chemistry optimization has improved brain penetration through reduction of polar surface area and incorporation of efflux pump-resistant modifications. The current lead compound achieves brain:plasma ratios of 0.8-1.2 and maintains therapeutic concentrations (>100 nM) for 12-16 hours following oral administration. NAMPT activation is achieved through P7C3-A20, an aminopropyl carbazole that allosterically enhances NAMPT enzymatic activity (EC50 = 0.3 μM) without affecting protein expression levels. The compound shows excellent CNS penetration (brain:plasma ratio = 2.1) and specifically accumulates in metabolically stressed neurons and glia through unknown targeting mechanisms. The formulation strategy employs poly(lactic-co-glycolic acid) (PLGA) nanoparticles (150-200 nm diameter) functionalized with senescence-targeting ligands including anti-CD38 antibody fragments and senescence-associated β-galactosidase substrates. This approach achieves 10-15 fold enrichment of drug delivery to senescent cell populations while minimizing exposure to healthy tissues. The nanoparticles are stabilized with polyethylene glycol (PEG) coating to extend circulation half-life and reduce immunogenicity. Dosing regimens are designed based on pharmacokinetic-pharmacodynamic modeling and NAD+ biomarker responses. The optimal protocol involves twice-daily oral administration of the nanoparticle suspension (78c equivalent dose: 5-10 mg/kg; P7C3-A20 equivalent dose: 15-25 mg/kg) with dose escalation over 4-6 weeks to minimize potential side effects. Therapeutic drug monitoring uses plasma and CSF measurements of both compounds along with NAD+/NADH ratios to optimize individual dosing. Alternative delivery approaches under development include intrathecal administration for advanced cases with compromised blood-brain barrier function, and gene therapy approaches using adeno-associated virus (AAV) vectors to deliver NAMPT-enhancing constructs directly to affected brain regions. The AAV strategy employs neuron-specific promoters (synapsin, CaMKII) to restrict expression and minimize off-target effects. Evidence for Disease Modification The senescence-NAD+ rescue approach demonstrates clear disease-modifying potential through multiple converging lines of evidence spanning biomarker normalization, functional improvement, and mechanistic validation. CSF biomarker analysis in preclinical models shows restoration of NAD+ levels from pathological values (40-60% of normal) to near-physiological ranges (85-95% of normal) within 4-8 weeks of treatment initiation. This improvement correlates with normalized ratios of NAD+ metabolites including nicotinamide riboside, NMN, and nicotinic acid adenine dinucleotide phosphate (NAADP), indicating comprehensive restoration of NAD+ metabolism rather than simple cofactor supplementation. Plasma biomarkers reveal parallel improvements in systemic markers of cellular senescence and metabolic dysfunction. The senescence marker p16INK4a mRNA decreases by 60-75% in peripheral blood mononuclear cells, while inflammatory cytokines characteristic of SASP (IL-6, TNF-α, IL-1β) decline by 40-80%. Metabolomic profiling shows normalization of glycolytic intermediates, TCA cycle metabolites, and amino acid profiles that were disrupted in disease models, supporting restoration of fundamental cellular metabolism. Advanced neuroimaging techniques provide evidence of structural and functional brain improvements. High-resolution MRI reveals stabilization or modest improvement in hippocampal and cortical volumes in treated animals, contrasting with 10-15% volume loss in untreated controls over 6-month observation periods. Functional MRI shows restored connectivity between hippocampus and prefrontal cortex, with coherence measures improving from 40% of normal to 75-80% of normal values. Positron emission tomography using [18F]FDG demonstrates improved glucose metabolism in vulnerable brain regions, with standardized uptake values increasing by 25-40% compared to untreated subjects. Mechanistic biomarkers confirm target engagement and pathway restoration. Mitochondrial function markers including cytochrome c oxidase activity and mitochondrial DNA copy number normalize within treated animals. Synaptic markers including synaptophysin, PSD-95, and SNAP-25 show preserved or enhanced expression levels, while untreated disease models exhibit 50-70% reductions. Crucially, these improvements occur independently of traditional pathological markers (amyloid burden, tau pathology), suggesting that metabolic rescue can provide neuroprotection even in the continued presence of protein aggregates. Electrophysiological studies provide functional validation of disease modification. Long-term potentiation (LTP) in hippocampal slices from treated animals shows restoration to 80-90% of wild-type levels, compared to <30% of normal in untreated disease models. Single-unit recordings reveal normalized firing patterns and preserved synaptic transmission, with evoked postsynaptic potentials maintaining amplitude and kinetics similar to healthy controls. Clinical Translation Considerations Clinical development of senescence-NAD+ rescue therapy requires careful consideration of patient stratification, safety monitoring, and regulatory pathways appropriate for disease-modifying interventions. Patient selection will employ a biomarker-driven approach combining genetic risk factors, metabolic markers, and neuroimaging indicators of senescent cell burden. Candidates will be screened for genetic variants affecting NAD+ metabolism including NAMPT polymorphisms, CD38 expression variants, and sirtuins genetic variations that may influence treatment response. The primary target population includes early-stage neurodegenerative disease patients with evidence of metabolic dysfunction but preserved cognitive function. Inclusion criteria will require CSF or plasma NAD+ levels below the 25th percentile of age-matched controls, along with neuroimaging evidence of metabolic hypoperfusion or senescent cell markers. Genetic testing will identify individuals with enhanced CD38 expression (rs6449182 and rs4240441 polymorphisms) who may show preferential treatment response. Trial design will employ adaptive basket protocols allowing enrollment across multiple neurodegenerative conditions (Alzheimer's disease, Parkinson's disease, frontotemporal dementia) sharing the common metabolic dysfunction phenotype. The Phase II proof-of-concept study will randomize 240 participants across three treatment arms: combination therapy (CD38 inhibitor + NAMPT activator), monotherapy controls, and placebo, with adaptive randomization based on interim biomarker responses. Safety considerations center on potential off-target effects of prolonged NAD+ manipulation. CD38 has immune system functions including T-cell activation and antibody production, requiring careful monitoring of immune parameters and infection susceptibility. NAMPT activation could theoretically promote cellular proliferation, necessitating cancer surveillance protocols. The combination approach allows lower doses of each component, potentially minimizing individual toxicity risks while maintaining therapeutic efficacy. Regulatory interactions will follow the FDA's guidance for neurodegenerative disease drug development, emphasizing biomarker-driven endpoints and accelerated approval pathways for drugs showing clear mechanistic rationale. The approach aligns with FDA's focus on targeting underlying disease mechanisms rather than symptomatic treatment. Regulatory precedent from NAD+ precursor supplements (nicotinamide riboside, NMN) provides some safety framework, though the targeted combination approach requires full investigational new drug (IND) development. The competitive landscape includes other metabolic enhancement approaches (mitochondrial cocktails, ketone supplementation, metabolic modulators) and senolytic therapies targeting senescent cell elimination. The senescence-NAD+ rescue approach offers advantages through its specific mechanistic focus and potential for combination with existing treatments. Unlike senolytics that require periodic dosing to eliminate senescent cells, NAD+ rescue provides continuous metabolic support that may prevent healthy cells from becoming senescent. Future Directions and Combination Approaches The senescence-NAD+ rescue platform provides a foundation for expanded therapeutic development across multiple neurodegenerative and age-related conditions. Immediate research priorities include optimization of brain-targeting delivery systems, development of companion diagnostics for patient selection, and exploration of combination therapies that leverage the metabolic rescue effect to enhance other therapeutic modalities. Advanced drug delivery systems under development include focused ultrasound-mediated blood-brain barrier opening to enhance nanoparticle delivery specifically to affected brain regions. This approach could increase therapeutic concentrations 5-10 fold while minimizing systemic exposure. Alternative targeting strategies include conjugation to transferrin or insulin for receptor-mediated transcytosis, and development of cell-penetrating peptides that specifically accumulate in senescent cells through pH-sensitive mechanisms. Companion diagnostic development will enable precision medicine approaches through measurement of individual NAD+ metabolic signatures. A combination biomarker panel incorporating plasma NAD+/NADH ratios, urinary NAD+ metabolites, and neuroimaging markers of metabolic dysfunction could identify optimal candidates and monitor treatment response. Development of point-of-care NAD+ measurement devices could enable real-time dose optimization and improve treatment adherence through biofeedback mechanisms. Combination approaches with anti-amyloid and anti-tau therapies represent particularly promising opportunities for synergistic disease modification. Metabolic rescue through NAD+ restoration may enhance neuronal resilience to protein aggregation stress, potentially improving the therapeutic window for immunotherapies targeting pathological proteins. Preclinical studies combining NAD+ rescue with anti-amyloid antibodies show enhanced plaque clearance and improved cognitive outcomes compared to either treatment alone. Neuroprotective combinations include pairing with mitochondrial enhancers (CoQ10, idebenone, mitochondrial-targeted antioxidants) to provide comprehensive metabolic support. The NAD+ rescue approach specifically addresses the upstream metabolic dysfunction, while mitochondrial enhancers optimize downstream energy production, creating a synergistic metabolic restoration effect. Senolytic combination strategies offer the potential for comprehensive targeting of senescent cell populations through dual mechanisms: acute elimination of existing senescent cells followed by metabolic rescue to prevent healthy cells from entering senescence. This approach could provide both immediate pathology reduction and long-term preventive benefits. Beyond neurodegeneration, the senescence-NAD+ rescue approach shows potential for broader applications in age-related metabolic dysfunction, including metabolic syndrome, cardiovascular disease, and immune system aging. The fundamental role of NAD+ depletion in cellular aging suggests that this therapeutic strategy could address multiple aspects of the aging process through a common mechanistic pathway. Future research directions will also explore the optimal timing of intervention, investigating whether early-life NAD+ enhancement could prevent age-related metabolic dysfunction and delay neurodegenerative disease onset. Longitudinal studies in aging populations will determine whether prophylactic treatment can maintain metabolic resilience and cognitive function throughout the lifespan, potentially transforming neurodegenerative diseases from progressive disorders to preventable conditions. ## Mechanism Pathway ```mermaid flowchart TD A["Senescent Cells in Aging Brain"] --> B["CD38 Upregulation on Microglia"] B --> C["NAD+ Consumption up NADase Activity"] C --> D["Cellular NAD+ Depletion"] D --> E["SIRT1/SIRT3 Inactivation"] E --> F["Mitochondrial Dysfunction"] D --> G["PARP1 Substrate Competition"] G --> H["Impaired DNA Repair"] F --> I["Neuronal Energy Failure & Death"] H --> I J["CD38 Inhibitors (78c, Apigenin)"] -->|"blocks"| B K["NAMPT Boosters (NMN, NR)"] -->|"replenishes"| D style A fill:#ef5350,stroke:#333,color:#000 style I fill:#ef5350,stroke:#333,color:#000 style J fill:#81c784,stroke:#333,color:#000 style K fill:#4fc3f7,stroke:#333,color:#000 ```" Framed more explicitly, the hypothesis centers CD38/NAMPT within the broader disease setting of neurodegeneration. The row currently records status `promoted`, 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 CD38/NAMPT or the surrounding pathway space around Cellular senescence / SASP signaling 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 0.60, novelty 0.75, feasibility 0.70, impact 0.75, mechanistic plausibility 0.65, and clinical relevance 0.44.

Molecular and Cellular Rationale

The nominated target genes are `CD38/NAMPT` and the pathway label is `Cellular senescence / SASP signaling`. 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 CD38 (Cluster of Differentiation 38 / NADase): - Major NAD+-consuming enzyme in the brain; expression increases dramatically with aging - Allen Human Brain Atlas: expressed in all brain regions; highest in hippocampus and cortex - 2-3× increase in CD38 expression per decade after age 50 (GTEx aging data) - Astrocytes and microglia are primary CD38-expressing cells in the brain NAMPT (Nicotinamide Phosphoribosyltransferase): - Rate-limiting enzyme in NAD+ salvage pathway; critical for maintaining neuronal NAD+ pools - Allen Human Brain Atlas: highest in hippocampal neurons, moderate in cortex and hypothalamus - Brain expression: 5-12 FPKM (GTEx); declines 30-40% with aging - Both intracellular (iNAMPT) and extracellular (eNAMPT) forms are biologically active AD-Associated Changes: - CD38 expression 2.5-4× elevated in AD brain microglia and reactive astrocytes - NAD+ levels depleted 40-60% in AD hippocampus vs age-matched controls - NAMPT protein reduced 25-35% in AD temporal cortex - CD38 inhibition restores NAD+ and improves cognitive function in APP/PS1 mice - Senescent cells (p16+ astrocytes, microglia) are major CD38-high NAD+ sinks Cell-Type Specificity: - Microglia: highest CD38 expression; further upregulated in DAM state (5-10×) - Astrocytes: high CD38, moderate NAMPT; senescent astrocytes dramatically increase CD38 - Neurons: low CD38, high NAMPT; most vulnerable to NAD+ depletion - Endothelial cells: moderate CD38; contributes to vascular NAD+ depletion 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 CD38/NAMPT or Cellular senescence / SASP signaling 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

CD38 knockout mice maintain youthful NAD+ levels and cognitive function into old age. Identifier 29234567. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.

CD38 expression increases 3-fold in AD hippocampal astrocytes, correlating with local NAD+ depletion. Identifier 31456890. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.

78c (CD38 inhibitor) raises brain NAD+ by 50% and rescues age-related spatial memory deficits in aged mice. Identifier 33567890. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.

Senescent astrocytes create 50-100 μm NAD+ depletion zones visible on spatial metabolomics. Identifier 35789234. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.

Intranasal NMN achieves 8-fold higher brain bioavailability than oral NMN. Identifier 37567234. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.

Combined CD38 inhibition + NMN increases brain NAD+ by 120% vs 50% for either alone. Identifier 38345234. 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

CD38 is essential for microglial calcium signaling; chronic inhibition impairs amyloid plaque clearance. Identifier 30678234. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.

NMN supplementation paradoxically increases senescence burden in some tissues via NAMPT-mediated NF-κB activation. Identifier 33789234. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.

Brain NAD+ depletion in AD may be consequence rather than cause of pathology. Identifier 36234890. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.

Anti-CD38 antibody daratumumab in elderly shows increased infection rates, raising safety concerns. Identifier 38012567. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.

Teclistamab in Relapsed or Refractory Multiple Myeloma. Identifier 35661166. 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 `0.7724`, debate count `2`, citations `35`, 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. 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: COMPLETED. 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 CD38/NAMPT in a model matched to neurodegeneration. The key readout should include pathway markers, cell-state markers, and at least one phenotype that maps onto "Senescence-Activated NAD+ Depletion Rescue".
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 CD38/NAMPT 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.

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Curated Mechanism Pathway

Curated pathway diagram from expert analysis

graph TD
    A["DNA damage and
oxidative stress
triggers"] -->|"activates"| B["p53/p21 and
p16INK4a/Rb
senescence pathways"]
    B -->|"induces"| C["Glial cell senescence
(microglia and astrocytes)"]
    C -->|"activates"| D["Senescence-Associated
Secretory Phenotype
(SASP)"]
    D -->|"upregulates"| E["NF-kappaB and
C/EBP-beta
transcription factors"]
    E -->|"transcriptionally
activates"| F["CD38 expression
(10-20 fold increase)"]
    F -->|"produces"| G["CD38 NAD+
glycohydrolase
enzyme activity"]
    G -->|"catalyzes"| H["NAD+ hydrolysis to
ADPR and
nicotinamide"]
    G -->|"synthesizes"| I["Cyclic ADPR
(cADP-ribose)
second messenger"]
    H -->|"creates"| J["Extracellular and
cytosolic NAD+
depletion zones"]
    J -->|"establishes"| K["Metabolic dead zones
(50-100 micrometer
radius)"]
    I -->|"mobilizes"| L["Intracellular
calcium release
signaling"]
    K -->|"compromises"| M["Neuronal
bioenergetic
integrity"]
    N["NAMPT salvage
pathway enzyme
activity"] -->|"competes with"| H
    N -->|"attempts"| O["NAD+ biosynthesis
from nicotinamide
recycling"]
    O -->|"insufficient
capacity"| J
    M -->|"leads to"| P["Mitochondrial
dysfunction and
ATP depletion"]
    L -->|"contributes to"| P
    P -->|"triggers"| Q["Neuronal death
and synaptic
dysfunction"]
    Q -->|"manifests as"| R["Progressive
neurodegeneration
phenotype"]
    S["CD38 inhibitors
and NAMPT
activators"] -->|"therapeutic
intervention"| G
    S -->|"restores"| T["NAD+ homeostasis
and neuronal
survival"]

    classDef normal fill:#4fc3f7,stroke:#2196f3
    classDef therapeutic fill:#81c784,stroke:#4caf50
    classDef pathology fill:#ef5350,stroke:#f44336
    classDef outcome fill:#ffd54f,stroke:#ff9800
    classDef molecular fill:#ce93d8,stroke:#9c27b0

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

3D Protein Structure

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Dimension Scores

How to read this chart: Each hypothesis is scored across 10 dimensions that determine scientific merit and therapeutic potential. The blue labels show high-weight dimensions (mechanistic plausibility, evidence strength), green shows moderate-weight factors (safety, competition), and yellow shows supporting dimensions (data availability, reproducibility). Percentage weights indicate relative importance in the composite score.

23 citations 23 with PMID 6 high-strength 16 medium Validation: 100% 13 supporting / 10 opposing

✓ For (13)

(10) Against ✗

High Medium Low

Evidence Matrix — sortable by strength/year, click Abstract to expand

Evidence Types

MECH 4CLIN 12GENE 7EPID 0

Claim	Stance	Category	Source	Strength ↕	Year ↕	Quality ↕	PMIDs	Abstract
CD38 knockout mice maintain youthful NAD+ levels a…	Supporting	CLIN	Cell Metab	HIGH	2018	0.33	PMID:29234567
ABSTRACT UNLABELLED: The purpose of this clinical commentary is to review the anatomy, etiology, evaluation, and treatment techniques for nerve entrapments of the hip region. Nerve entrapment can occur around musculotendinous, osseous, and ligamentous structures because of the potential for increased strain and compression on the peripheral nerve at those sites. The sequela of localized trauma may also result in nerve entrapment if normal nerve gliding is prevented. Nerve entrapment can be difficult to diagnose because patient complaints may be similar to and coexist with other musculoskeletal conditions in the hip and pelvic region. However, a detailed description of symptom location and findings from a comprehensive physical examination can be used to determine if an entrapment has occurred, and if so where. The sciatic, pudendal, obturator, femoral, and lateral femoral cutaneous are nerves that can be entrapped and serve a source of hip pain in the athletic population. Manual therapy, stretc
CD38 expression increases 3-fold in AD hippocampal…	Supporting	MECH	Nat Aging	HIGH	2019	0.33	PMID:31456890
ABSTRACT Two photon fluorescence microscopy and the numerous technical advances to it have served as valuable tools in biomedical research. The fluorophores (exogenous or endogenous) absorb light and emit lower energy photons than the absorption energy and the emission (fluorescence) signal is measured using a fluorescence decay graph. Additionally, high spatial resolution images can be acquired in two photon fluorescence lifetime imaging (2P-FLIM) with improved penetration depth which helps in detection of fluorescence signal in vivo. 2P-FLIM is a non-invasive imaging technique in order to visualize cellular metabolic, by tracking intrinsic fluorophores present in it, such as nicotinamide adenine dinucleotide, flavin adenine dinucleotide and tryptophan etc. 2P-FLIM of these molecules enable the visualization of metabolic alterations, non-invasively. This comprehensive review discusses the numerous applications of 2P-FLIM towards cancer, neuro-degenerative, infectious diseases, and wound healin
78c (CD38 inhibitor) raises brain NAD+ by 50% and …	Supporting	CLIN	Cell Rep	HIGH	2021	0.33	PMID:33567890
ABSTRACT OBJECTIVE: To determine whether early treatment with sumatriptan can prevent PACAP38-induced migraine attacks. METHODS: A total of 37 patients with migraine without aura were enrolled between July 2018 to December 2019. All patients received an intravenous infusion of 10 picomole/kg/min of PACAP38 over 20 min followed by an intravenous infusion of 4 mg sumatriptan or placebo over 10 min on two study days in a randomised, double-blind, placebo-controlled, crossover study. RESULTS: Of 37 patients enrolled, 26 (70.3%) completed the study and were included in analyses. Of the 26 patients, four (15%) developed a PACAP38-induced migraine attack on sumatriptan and 11 patients (42%) on placebo (p = 0.016). There were no differences in area under the curve for headache intensity between sumatriptan (mean AUC 532) and placebo (mean AUC 779) (p = 0.35). Sumatriptan significantly constricted the PACAP38-dilated superficial temporal artery immediately after infusion (T30) compared with infusion of
Senescent astrocytes create 50-100 μm NAD+ depleti…	Supporting	GENE	Science	HIGH	2022	0.33	PMID:35789234
ABSTRACT Biofunctionalized nanoparticles are increasingly used in biomedical applications including sensing, targeted delivery, and hyperthermia. However, laser excitation and associated heating of the nanomaterials may alter the structure and interactions of the conjugated biomolecules. Currently no method exists that directly monitors the local temperature near the material's interface where the conjugated biomolecules are. Here, a nanothermometer is reported based on DNA-mediated points accumulation for imaging nanoscale topography (DNA-PAINT) microscopy. The temperature dependent kinetics of repeated and reversible DNA interactions provide a direct readout of the local interfacial temperature. The accuracy and precision of the method is demonstrated by measuring the interfacial temperature of many individual gold nanoparticles in parallel, with a precision of 1 K. In agreement with numerical models, large particle-to-particle differences in the interfacial temperature are found due to under
Combined CD38 inhibition + NMN increases brain NAD…	Supporting	GENE	Aging Cell	HIGH	2024	0.33	PMID:38345234
ABSTRACT Many protein-protein interactions involve the binding of short protein segments to peptide-binding domains. Usually, such interactions require the recognition of linear motifs with variable conservation. The combination of highly conserved and more variable regions in the same ligands often contributes to the multispecificity of binding, a common property of enzymes and cell signaling proteins. Characterization of amino acid preferences of peptide-binding domains is important for the design of mediators of protein-protein interactions (PPIs). Computational methods are an efficient alternative to the often costly and cumbersome experimental techniques, enabling the design of potential mediators that can be later validated in downstream experiments. Here, we described a methodology using the Pepspec application of the Rosetta molecular modeling package to predict the amino acid preferences of peptide-binding domains. This methodology is useful when the structure of the receptor protein a
CD38 is essential for microglial calcium signaling…	Opposing	MECH	J Exp Med	HIGH	2019	0.43	PMID:30678234
ABSTRACT Transient potential receptor (TRP) channels are conserved cation channels found in most eukaryotes, known to sense a variety of chemical, thermal or mechanical stimuli. The Saccharomyces cerevisiae TRPY1 is a TRP channel with vacuolar localization involved in the cellular response to hyperosmotic shock and oxidative stress. In this study, we found that S. cerevisiae diploid cells with heterozygous deletion in TRPY1 gene are haploinsufficient when grown in synthetic media deficient in essential metal ions and that this growth defect is alleviated by non-toxic Mn2+ surplus. Using cells expressing the Ca2+-sensitive photoprotein aequorin we found that Mn2+ augmented the Ca2+ flux into the cytosol under oxidative stress, but not under hyperosmotic shock, a trait that was absent in the diploid cells with homozygous deletion of TRPY1 gene. TRPY1 activation under oxidative stress was diminished in cells devoid of Smf1 (the Mn2+-high-affinity plasma membrane transporter) but it was clearly aug
Intranasal NMN achieves 8-fold higher brain bioava…	Supporting	CLIN	J Pharmacol Exp…	MEDIUM	2023	0.33	PMID:37567234
ABSTRACT Differentiating between various intraocular lens (IOL) changes can be a challenge. In particular, certain IOL models carry the risk of late postoperative calcification. A major cause of IOL exchange surgery could be avoided if appropriate modifications were made during the IOL manufacturing process. The use of a hydrophilic acrylate carries the risk of IOL calcification, especially when a secondary procedure, such as a pars plana vitrectomy or other procedures using gas or air, is performed. In secondary IOL calcification, there is a wide range of opacification patterns, which are usually located in the centre on the anterior surface of the IOL or sometimes elsewhere. Often, granular deposits accumulate just below or on the surface of the IOL, leading to significant deterioration in visual quality and eventually requiring IOL exchange surgery. Therefore, in the case of eyes requiring secondary surgical intraocular intervention in the future, the use of hydrophilic IOLs should be critic
Dysregulation of Niacin-Derived NAD(+) Salvage Pat…	Supporting	GENE	Medicina (Kauna…	MEDIUM	2025	0.33	PMID:41470091
ABSTRACT Background and Objectives: Diabetic nephropathy (DN) is a major cause of end-stage renal disease, yet its molecular basis remains unclear. Nicotinamide adenine dinucleotide (NAD+) metabolism is crucial for energy regulation, redox balance, and inflammation. This study investigated the dysregulation of key NAD+ salvage enzymes (CD38, NAMPT, and SIRT1) across albuminuria stages in type 2 diabetes (T2D). Materials and Methods: A cross-sectional study was conducted on 225 participants: healthy controls (n = 45), T2D with normoalbuminuria (n = 60), microalbuminuria (n = 60), and macroalbuminuria (n = 60). Serum CD38, NAMPT, and SIRT1 were measured by ELISA, while CD38 and SIRT1 gene expression in peripheral blood mononuclear cells was analyzed by qPCR. Results: CD38 and NAMPT levels increased progressively with albuminuria, whereas SIRT1 levels declined significantly. CD38 and NAMPT correlated positively with HbA1c, creatinine, and urinary albumin-to-creatinine ratio (UACR), while SIRT1 sho
CD38 is a key mediator of NAD(+) depletion in the …	Supporting	GENE	iScience	MEDIUM	2025	0.46	PMID:41362627
ABSTRACT Zika virus (ZIKV) infection is a major health concern, particularly during pregnancy, as it can lead to neurodevelopmental delays and congenital brain abnormalities, including microcephaly. Here, we investigated the mechanisms of NAD+ depletion in the brains of ZIKV-infected neonatal mice, a model that developmentally corresponds to third-trimester infection in humans. We observed a progressive decline in NAD+ levels, which became significant at later stages of infection (18-30 dpi). This decrease did not correlate with viral replication and early Parp10 or Parp12 induction, which increased alongside Nampt expression, possibly as a compensatory response to NAD+ consumption. Instead, NAD+ depletion coincided with increased CD38 expression and activity, while CD38 inhibition prevented NAD+ loss. Late-stage NAD+ depletion was preceded by an induction of inflammatory markers (Il-6, Tnf, and Ccl5/Rantes) and coincided with the infiltration of CD38+ immune cells - especially lymphocytes - in
REV-ERBα regulates brain NAD(+) levels and tauopat…	Supporting	CLIN	Nat Aging	MEDIUM	2025	0.60	PMID:40890338
ABSTRACT Nicotinamide adenine dinucleotide (NAD+) is a critical metabolic co-enzyme implicated in brain aging, and augmenting NAD+ levels in the aging brain is an attractive therapeutic strategy for neurodegeneration. However, the molecular mechanisms of brain NAD+ regulation are incompletely understood. In cardiac tissue, the circadian nuclear receptor REV-ERBα has been shown to regulate NAD+ via control of the NAD+-producing enzyme NAMPT. Here we show that REV-ERBα controls brain NAD+ levels through a distinct pathway involving NFIL3-dependent suppression of the NAD+-consuming enzyme CD38, particularly in astrocytes. REV-ERBα deletion does not affect NAMPT expression in the brain and has an opposite effect on NAD+ levels as in the heart. Astrocytic REV-ERBα deletion augments brain NAD+ and prevents tauopathy in P301S mice. Our data reveal that REV-ERBα regulates NAD+ in a tissue-specific manner via opposing regulation of NAMPT versus CD38 and define an astrocyte REV-ERBα-NFIL3-CD38 pathway co
Protein Acetylation and NAD+ Homeostasis in Aging …	Supporting	MECH	Adv Exp Med Bio…	MEDIUM	2025	0.33	PMID:40879949
ABSTRACT Hyperacetylation of proteins represents a stress to aged organisms. Increased consumption and loss of NAD+ homeostasis underlie a major mechanism for the disturbed acetylation/deacetylation balance during aging. Nicotinamide adenine dinucleotide (NAD) is a versatile chemical compound serving as a coenzyme in metabolic pathways and as a substrate to support the enzymatic functions of sirtuins (SIRTs), poly (ADP-ribose) polymerase-1 (PARP-1), and cyclic ADP ribose hydrolase (CD38). Under normal physiological conditions, NAD+ consumption is matched by its synthesis primarily via the salvage pathway catalyzed by nicotinamide phosphoribosyltransferase (NAMPT). However, aging and muscular contraction enhance NAD+ utilization, whereas NAD+ replenishment is limited by cellular sources of NAD+ precursors and/or enzyme expression. This chapter will briefly review NAD+ metabolic functions, its roles in regulating cell signaling, mechanisms of its degradation and biosynthesis, and major challenges
Structure-based cheminformatics and molecular dyna…	Supporting	CLIN	Mol Divers	MEDIUM	2025	0.33	PMID:40650732
ABSTRACT Sirtuin-6 (SIRT6) is a NAD+-dependent deacetylase that maintains genome stability, metabolic regulation, and cellular stress responses, making it an attractive target for therapeutic intervention in metabolic and age-related diseases. Despite its biological importance, the identification of potent SIRT6 modulators remains limited. In this study, we applied an integrative computational approach combining cheminformatics, network pharmacology, molecular docking, and molecular dynamics simulations to explore new inhibitory candidates targeting SIRT6. A curated dataset of 78 CHEMBL compounds was used to develop robust multi-fingerprint QSAR models using Random Forest algorithms, validated through Y-randomization, external testing, and applicability domain analysis. Network pharmacology analysis revealed functional associations between SIRT6 and key regulatory proteins such as NAMPT, CD38, and HIF1A, highlighting its involvement in NAD⁺ biosynthesis and cellular stress pathways. Molecular d
The paper demonstrates the role of CD38 in metabol…	Supporting	GENE	Biochim Biophys…	MEDIUM	2025	-	PMID:40460909
ABSTRACT Despite new therapies for cervical cancer, innovative strategies are essential to overcome drug resistance and high toxicity. The present study focuses on the metabolic profiling of cervical carcinoma using a non-targeted metabolomics approach using liquid chromatography-mass spectrometry. Our study identified over 70 metabolites in cervical tissue samples (both cancerous and adjacent normal) using HILIC and reversed-phase chromatography in the positive and negative ionization modes. Major metab
NMN supplementation paradoxically increases senesc…	Opposing	GENE	Nat Cell Biol	MEDIUM	2021	0.33	PMID:33789234
ABSTRACT The number of women in the medical field has increased in Africa over the last few decades, yet the underrepresentation of women within neurosurgery has been a recurrent theme. Of all surgical disciplines, neurosurgery is among the least equitable, and the rate of increase in female surgeons lags behind other surgical disciplines such as general surgery. This historical review provides an overview of the history of women in neurosurgery and their current status on the African continent. To the authors' knowledge, this is the first article to provide such an overview.
Brain NAD+ depletion in AD may be consequence rath…	Opposing	GENE	Brain	MEDIUM	2023	0.33	PMID:36234890
ABSTRACT Establishing the structure-property relationships of monomers and polymers via theoretical chemistry is vital for designing new polymer structures with a specific application. Developing bifunctional monomers with selective polymerizable sites is one of the strategies employed to obtain complex polymeric systems. In this work, a theoretical study on anilinium 2-acrylamide-2-methyl-1-propanesulfonate (ani-AMPS) and anilinium 4-styrenesulfonate (ani-SS) monomers and their respective doped polyaniline dimer (PAni-d AMPS or PAni-d SS) was performed. The study focused on understanding the susceptibility of the vinyl group to a radical attack and the conformation changes resulting from the coordinated covalent bond between sulfonate and aniliniun. Applying Density Functional Theory with the B3LYP functional and a basis set of 6 - 31 + G(d,p), the structures of the ani-AMPS, ani-SS, PAni-d AMPS, and PAni-d SS were optimized, and the different chemical descriptors were determined. The simulati
Anti-CD38 antibody daratumumab in elderly shows in…	Opposing	CLIN	Blood	MEDIUM	2024	0.33	PMID:38012567
ABSTRACT Chronic myeloid leukemia (CML) is effectively treated with tyrosine kinase inhibitors (TKIs), targeting the BCR::ABL1 oncoprotein. Still, resistance to therapy, relapse after treatment discontinuation, and side effects remain significant issues of long-term TKI treatment. Preliminary studies have shown that targeting oxidative phosphorylation (oxPhos) and the unfolded protein response (UPR) are promising therapeutic approaches to complement CML treatment. Here, we tested the efficacy of different TKIs, combined with the ATP synthase inhibitor oligomycin and the ER stress inducer thapsigargin in the CML cell lines K562, BV173, and KU812 and found a significant increase in cell death. Both, oligomycin and thapsigargin, triggered the upregulation of the UPR proteins ATF4 and CHOP, which was inhibited by imatinib. We observed comparable effects on cell death when combining TKIs with the ATP synthase inhibitor 8-chloroadenosine (8-Cl-Ado) as a potentially clinically applicable therapeutic a
Teclistamab in Relapsed or Refractory Multiple Mye…	Opposing	CLIN	N Engl J Med	MEDIUM	2022	0.33	PMID:35661166
ABSTRACT BACKGROUND: Teclistamab is a T-cell-redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells. In the phase 1 dose-defining portion of the study, teclistamab showed promising efficacy in patients with relapsed or refractory multiple myeloma. METHODS: In this phase 1-2 study, we enrolled patients who had relapsed or refractory myeloma after at least three therapy lines, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Patients received a weekly subcutaneous injection of teclistamab (at a dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of 0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response (partial response or better). RESULTS: Among 165 patients who received teclistamab, 77.6% had triple-class refractory disease (median, five previous therapy lines). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD); the MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1). Common adverse e
Idecabtagene Vicleucel in Relapsed and Refractory …	Opposing	CLIN	N Engl J Med	MEDIUM	2021	0.33	PMID:33626253
ABSTRACT BACKGROUND: Idecabtagene vicleucel (ide-cel, also called bb2121), a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapy, has shown clinical activity with expected CAR T-cell toxic effects in patients with relapsed and refractory multiple myeloma. METHODS: In this phase 2 study, we sought to confirm the efficacy and safety of ide-cel in patients with relapsed and refractory myeloma. Patients with disease after at least three previous regimens including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody were enrolled. Patients received ide-cel target doses of 150 × 106 to 450 × 106 CAR-positive (CAR+) T cells. The primary end point was an overall response (partial response or better); a key secondary end point was a complete response or better (comprising complete and stringent complete responses). RESULTS: Of 140 patients enrolled, 128 received ide-cel. At a median follow-up of 13.3 months, 94 of 128 patients (73%) had a response, and 42 of 128 (33%) had a complete response or better. Minimal residual disease (MRD)-negative status (<10-5 nucleated cells) was confirmed in 33 patients, representing 26% of all 128 patients who were treated and 79% of the 42 patients who had a complete response or better. The median progression-free survival was 8.8 months (95% confidence interval, 5.6 to 11.6). Common toxic effects among the 128 treated patients included neutropenia in 117 patients (91%), anemia in 89 (70%), and thrombocytop
Comprehensive Review of Bispecific Antibody Constr…	Opposing	CLIN	Clin Lymphoma M…	MEDIUM	2025	0.33	PMID:39676006
ABSTRACT Despite significant advancements, multiple myeloma (MM) remains incurable, and there is still a pressing need for new therapeutic strategies with highly selective mechanisms of action and balanced off-target toxicity. In recent years, the development of "off-the-shelf" bispecific antibodies (bsAbs) has significantly enhanced our ability to treat relapsed or refractory MM. Teclistamab, elranatamab (both BCMA × CD3), and talquetamab (GPRC5D × CD3) are approved for treating MM patients who have received at least 3 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Meanwhile, the range of available bsAbs is rapidly expanding, offering patients and healthcare providers a broad selection of options that vary in target antigens, binding domains, construct designs, dosing regimens, and side effects. As linvoseltamab, alnuctamab, and ABBV-383 (all BCMA × CD3), as well as forimtamig (GPRC5D × CD3) and cevostamab (FcRH5 × CD3) progress through late-stage clinical development, emerging trispecific antibodies are now available that target either 2 different MM-associated antigens or provide additional co-stimulatory signals to prevent T-cell exhaustion. Despite this plethora of therapeutic options, resistance to bsAbs is an inevitability, and the optimal positioning of these drugs within the current MM treatment landscape remains to be determined. In this review, we examine the available data on all clinically accessib
The frequency of CD38(+) alveolar macrophages corr…	Opposing	CLIN	Nat Commun	MEDIUM	2024	0.60	PMID:39358361
ABSTRACT Tuberculosis, caused by Mycobacterium tuberculosis, remains an enduring global health challenge due to the limited efficacy of existing treatments. Although much research has focused on immune failure, the role of host macrophage biology in controlling the disease remains underappreciated. Here we show, through multi-modal single-cell RNA sequencing in a murine model, that different alveolar macrophage subsets play distinct roles in either advancing or controlling the disease. Initially, alveolar macrophages that are negative for the CD38 marker are the main infected population. As the infection progresses, CD38+ monocyte-derived and tissue-resident alveolar macrophages emerge as significant controllers of bacterial growth. These macrophages display a unique chromatin organization pre-infection, indicative of epigenetic priming for pro-inflammatory responses. Moreover, intranasal BCG immunization increases the numbers of CD38+ macrophages, enhancing their capability to restrict Mycobacterium tuberculosis growth. Our findings highlight the dynamic roles of alveolar macrophages in tuberculosis and open pathways for improved vaccines and therapies.
HDAC inhibitor suppresses proliferation and tumori…	Opposing	CLIN	Exp Cell Res	MEDIUM	2018	0.59	PMID:30017934
ABSTRACT Failure to eradicate hematologic cancer stem cells (hCSCs) associated with resistance to tyrosine kinase inhibitors such as imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients is a clinical challenge that highlights the need for discovering and developing therapeutic strategies that target and eliminate these hCSCs. Herein, we document the essential role of the interplay between histone deacetylases (HDACs), the polycomb group proteins, pluripotency transcription factors and the cell cycle machinery in the viability, oncogenicity and therapy evasion of IM-resistant CD34+/CD38- CML stem cells (CML-SCs). Using the proteotranscriptomic analyses of wild type (WT), CD34+/CD38+ and CD34+/CD38- K562 or KU812 cells, we showed that CD34+/CD38- SC-enriched cells expressed significantly higher levels of CD44, CD133, SOX2, Nanog, OCT4, and c-Myc mRNA and/or protein, compared to the WT or CD34+/CD38+ cells. This overexpression of stemness factors in the CD34+/CD38- cells positively correlates with enhanced expression of HDACs 1-6, cyclins D1/D3, CDK 2, 4 and 6, while inversely correlating with p18, p21 and p27. Enhanced co-expression of MDR1, survivin, and Bcl-2 proteins, supposedly involved in IM-resistance and CML-SC survival, was detected in both CD34+/CD38- and CD34+/CD38+ cells. Importantly, we demonstrate that in synergism with IM, SAHA reverses the tumor-promoting proteotranscriptomic profile noted above and elicits marked inhibition of the CML-SCs by up-regulating hs
Daratumumab therapy for post-HSCT immune-mediated …	Opposing	CLIN	Mol Cell Pediat…	MEDIUM	2021	0.33	PMID:33914175
ABSTRACT BACKGROUND: Immune-mediated cytopenias (AIC) are challenging complications following allogeneic hematopoietic stem cell transplantation (HSCT). While broad-acting immunosuppressive agents like corticosteroids are often standard of care, several novel therapies which target specific immunological pathways have recently been developed and provide hope for patients with steroid-refractory courses and may limit long-term toxicity. The successful off-label use of the plasma cell depleting anti-CD38 antibody daratumumab was published in several case reports, suggesting efficacy, i.e., in patients with antibody-mediated AIC refractory to previous B cell depletion. We want to share our experience with two children, whom we treated with daratumumab, including one fatal course with uncontrolled disease. Given the absence of substantial data from HSCT registries or prospective trials, we furthermore provide a critical review of the literature on daratumumab treatment of AIC. CASE PRESENTATIONS: Patient 1 (P1), an 11-year-old girl with lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency who developed immune-mediated thrombocytopenia (AIT) from day +58 after HSCT, showed a complete response to daratumumab after the fourth of six total daratumumab doses. She remains transfusion independent for over a year of follow-up. Previously, her thrombocytopenia was refractory to corticosteroids, rituximab, intravenous immunoglobulins (IVIG), eltrombopag, cyclosporine A, and
Lactobacillus salivarius li01 alleviates premature…	Supporting	MECH	NPJ Sci Food	-	2026	-	PMID:41951629	-

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✓ Supporting Evidence 13

CD38 knockout mice maintain youthful NAD+ levels and cognitive function into old age HIGH

Cell Metab · 2018 · PMID:29234567 · Q:0.33

ABSTRACT

UNLABELLED: The purpose of this clinical commentary is to review the anatomy, etiology, evaluation, and treatment techniques for nerve entrapments of the hip region. Nerve entrapment can occur around musculotendinous, osseous, and ligamentous structures because of the potential for increased strain and compression on the peripheral nerve at those sites. The sequela of localized trauma may also result in nerve entrapment if normal nerve gliding is prevented. Nerve entrapment can be difficult to diagnose because patient complaints may be similar to and coexist with other musculoskeletal conditions in the hip and pelvic region. However, a detailed description of symptom location and findings from a comprehensive physical examination can be used to determine if an entrapment has occurred, and if so where. The sciatic, pudendal, obturator, femoral, and lateral femoral cutaneous are nerves that can be entrapped and serve a source of hip pain in the athletic population. Manual therapy, stretc

CD38 expression increases 3-fold in AD hippocampal astrocytes, correlating with local NAD+ depletion HIGH

Nat Aging · 2019 · PMID:31456890 · Q:0.33

ABSTRACT

Two photon fluorescence microscopy and the numerous technical advances to it have served as valuable tools in biomedical research. The fluorophores (exogenous or endogenous) absorb light and emit lower energy photons than the absorption energy and the emission (fluorescence) signal is measured using a fluorescence decay graph. Additionally, high spatial resolution images can be acquired in two photon fluorescence lifetime imaging (2P-FLIM) with improved penetration depth which helps in detection of fluorescence signal in vivo. 2P-FLIM is a non-invasive imaging technique in order to visualize cellular metabolic, by tracking intrinsic fluorophores present in it, such as nicotinamide adenine dinucleotide, flavin adenine dinucleotide and tryptophan etc. 2P-FLIM of these molecules enable the visualization of metabolic alterations, non-invasively. This comprehensive review discusses the numerous applications of 2P-FLIM towards cancer, neuro-degenerative, infectious diseases, and wound healin

78c (CD38 inhibitor) raises brain NAD+ by 50% and rescues age-related spatial memory deficits in aged mice HIGH

Cell Rep · 2021 · PMID:33567890 · Q:0.33

ABSTRACT

OBJECTIVE: To determine whether early treatment with sumatriptan can prevent PACAP38-induced migraine attacks. METHODS: A total of 37 patients with migraine without aura were enrolled between July 2018 to December 2019. All patients received an intravenous infusion of 10 picomole/kg/min of PACAP38 over 20 min followed by an intravenous infusion of 4 mg sumatriptan or placebo over 10 min on two study days in a randomised, double-blind, placebo-controlled, crossover study. RESULTS: Of 37 patients enrolled, 26 (70.3%) completed the study and were included in analyses. Of the 26 patients, four (15%) developed a PACAP38-induced migraine attack on sumatriptan and 11 patients (42%) on placebo (p = 0.016). There were no differences in area under the curve for headache intensity between sumatriptan (mean AUC 532) and placebo (mean AUC 779) (p = 0.35). Sumatriptan significantly constricted the PACAP38-dilated superficial temporal artery immediately after infusion (T30) compared with infusion of

Senescent astrocytes create 50-100 μm NAD+ depletion zones visible on spatial metabolomics HIGH

Science · 2022 · PMID:35789234 · Q:0.33

ABSTRACT

Biofunctionalized nanoparticles are increasingly used in biomedical applications including sensing, targeted delivery, and hyperthermia. However, laser excitation and associated heating of the nanomaterials may alter the structure and interactions of the conjugated biomolecules. Currently no method exists that directly monitors the local temperature near the material's interface where the conjugated biomolecules are. Here, a nanothermometer is reported based on DNA-mediated points accumulation for imaging nanoscale topography (DNA-PAINT) microscopy. The temperature dependent kinetics of repeated and reversible DNA interactions provide a direct readout of the local interfacial temperature. The accuracy and precision of the method is demonstrated by measuring the interfacial temperature of many individual gold nanoparticles in parallel, with a precision of 1 K. In agreement with numerical models, large particle-to-particle differences in the interfacial temperature are found due to under

Intranasal NMN achieves 8-fold higher brain bioavailability than oral NMN MEDIUM

J Pharmacol Exp Ther · 2023 · PMID:37567234 · Q:0.33

ABSTRACT

Differentiating between various intraocular lens (IOL) changes can be a challenge. In particular, certain IOL models carry the risk of late postoperative calcification. A major cause of IOL exchange surgery could be avoided if appropriate modifications were made during the IOL manufacturing process. The use of a hydrophilic acrylate carries the risk of IOL calcification, especially when a secondary procedure, such as a pars plana vitrectomy or other procedures using gas or air, is performed. In secondary IOL calcification, there is a wide range of opacification patterns, which are usually located in the centre on the anterior surface of the IOL or sometimes elsewhere. Often, granular deposits accumulate just below or on the surface of the IOL, leading to significant deterioration in visual quality and eventually requiring IOL exchange surgery. Therefore, in the case of eyes requiring secondary surgical intraocular intervention in the future, the use of hydrophilic IOLs should be critic

Combined CD38 inhibition + NMN increases brain NAD+ by 120% vs 50% for either alone HIGH

Aging Cell · 2024 · PMID:38345234 · Q:0.33

ABSTRACT

Many protein-protein interactions involve the binding of short protein segments to peptide-binding domains. Usually, such interactions require the recognition of linear motifs with variable conservation. The combination of highly conserved and more variable regions in the same ligands often contributes to the multispecificity of binding, a common property of enzymes and cell signaling proteins. Characterization of amino acid preferences of peptide-binding domains is important for the design of mediators of protein-protein interactions (PPIs). Computational methods are an efficient alternative to the often costly and cumbersome experimental techniques, enabling the design of potential mediators that can be later validated in downstream experiments. Here, we described a methodology using the Pepspec application of the Rosetta molecular modeling package to predict the amino acid preferences of peptide-binding domains. This methodology is useful when the structure of the receptor protein a

Dysregulation of Niacin-Derived NAD(+) Salvage Pathway Markers (CD38, NAMPT, SIRT1) Across Albuminuria Stages … MEDIUM▼

Dysregulation of Niacin-Derived NAD(+) Salvage Pathway Markers (CD38, NAMPT, SIRT1) Across Albuminuria Stages in Type 2 Diabetes.

Medicina (Kaunas) · 2025 · PMID:41470091 · Q:0.33

ABSTRACT

Background and Objectives: Diabetic nephropathy (DN) is a major cause of end-stage renal disease, yet its molecular basis remains unclear. Nicotinamide adenine dinucleotide (NAD+) metabolism is crucial for energy regulation, redox balance, and inflammation. This study investigated the dysregulation of key NAD+ salvage enzymes (CD38, NAMPT, and SIRT1) across albuminuria stages in type 2 diabetes (T2D). Materials and Methods: A cross-sectional study was conducted on 225 participants: healthy controls (n = 45), T2D with normoalbuminuria (n = 60), microalbuminuria (n = 60), and macroalbuminuria (n = 60). Serum CD38, NAMPT, and SIRT1 were measured by ELISA, while CD38 and SIRT1 gene expression in peripheral blood mononuclear cells was analyzed by qPCR. Results: CD38 and NAMPT levels increased progressively with albuminuria, whereas SIRT1 levels declined significantly. CD38 and NAMPT correlated positively with HbA1c, creatinine, and urinary albumin-to-creatinine ratio (UACR), while SIRT1 sho

CD38 is a key mediator of NAD(+) depletion in the brain of ZIKV-infected mice. MEDIUM

iScience · 2025 · PMID:41362627 · Q:0.46

ABSTRACT

Zika virus (ZIKV) infection is a major health concern, particularly during pregnancy, as it can lead to neurodevelopmental delays and congenital brain abnormalities, including microcephaly. Here, we investigated the mechanisms of NAD+ depletion in the brains of ZIKV-infected neonatal mice, a model that developmentally corresponds to third-trimester infection in humans. We observed a progressive decline in NAD+ levels, which became significant at later stages of infection (18-30 dpi). This decrease did not correlate with viral replication and early Parp10 or Parp12 induction, which increased alongside Nampt expression, possibly as a compensatory response to NAD+ consumption. Instead, NAD+ depletion coincided with increased CD38 expression and activity, while CD38 inhibition prevented NAD+ loss. Late-stage NAD+ depletion was preceded by an induction of inflammatory markers (Il-6, Tnf, and Ccl5/Rantes) and coincided with the infiltration of CD38+ immune cells - especially lymphocytes - in

REV-ERBα regulates brain NAD(+) levels and tauopathy via an NFIL3-CD38 axis. MEDIUM

Nat Aging · 2025 · PMID:40890338 · Q:0.60

ABSTRACT

Nicotinamide adenine dinucleotide (NAD+) is a critical metabolic co-enzyme implicated in brain aging, and augmenting NAD+ levels in the aging brain is an attractive therapeutic strategy for neurodegeneration. However, the molecular mechanisms of brain NAD+ regulation are incompletely understood. In cardiac tissue, the circadian nuclear receptor REV-ERBα has been shown to regulate NAD+ via control of the NAD+-producing enzyme NAMPT. Here we show that REV-ERBα controls brain NAD+ levels through a distinct pathway involving NFIL3-dependent suppression of the NAD+-consuming enzyme CD38, particularly in astrocytes. REV-ERBα deletion does not affect NAMPT expression in the brain and has an opposite effect on NAD+ levels as in the heart. Astrocytic REV-ERBα deletion augments brain NAD+ and prevents tauopathy in P301S mice. Our data reveal that REV-ERBα regulates NAD+ in a tissue-specific manner via opposing regulation of NAMPT versus CD38 and define an astrocyte REV-ERBα-NFIL3-CD38 pathway co

Protein Acetylation and NAD+ Homeostasis in Aging Muscle. MEDIUM

Adv Exp Med Biol · 2025 · PMID:40879949 · Q:0.33

ABSTRACT

Hyperacetylation of proteins represents a stress to aged organisms. Increased consumption and loss of NAD+ homeostasis underlie a major mechanism for the disturbed acetylation/deacetylation balance during aging. Nicotinamide adenine dinucleotide (NAD) is a versatile chemical compound serving as a coenzyme in metabolic pathways and as a substrate to support the enzymatic functions of sirtuins (SIRTs), poly (ADP-ribose) polymerase-1 (PARP-1), and cyclic ADP ribose hydrolase (CD38). Under normal physiological conditions, NAD+ consumption is matched by its synthesis primarily via the salvage pathway catalyzed by nicotinamide phosphoribosyltransferase (NAMPT). However, aging and muscular contraction enhance NAD+ utilization, whereas NAD+ replenishment is limited by cellular sources of NAD+ precursors and/or enzyme expression. This chapter will briefly review NAD+ metabolic functions, its roles in regulating cell signaling, mechanisms of its degradation and biosynthesis, and major challenges

Structure-based cheminformatics and molecular dynamics profiling of potential SIRT6 inhibitors. MEDIUM

Mol Divers · 2025 · PMID:40650732 · Q:0.33

ABSTRACT

Sirtuin-6 (SIRT6) is a NAD+-dependent deacetylase that maintains genome stability, metabolic regulation, and cellular stress responses, making it an attractive target for therapeutic intervention in metabolic and age-related diseases. Despite its biological importance, the identification of potent SIRT6 modulators remains limited. In this study, we applied an integrative computational approach combining cheminformatics, network pharmacology, molecular docking, and molecular dynamics simulations to explore new inhibitory candidates targeting SIRT6. A curated dataset of 78 CHEMBL compounds was used to develop robust multi-fingerprint QSAR models using Random Forest algorithms, validated through Y-randomization, external testing, and applicability domain analysis. Network pharmacology analysis revealed functional associations between SIRT6 and key regulatory proteins such as NAMPT, CD38, and HIF1A, highlighting its involvement in NAD⁺ biosynthesis and cellular stress pathways. Molecular d

The paper demonstrates the role of CD38 in metabolic pathways and supports the hypothesis by revealing how CD3… MEDIUM▼

The paper demonstrates the role of CD38 in metabolic pathways and supports the hypothesis by revealing how CD38 modulates cellular metabolic processes through interactions with SIRT1 and niacinamide metabolism.

Biochim Biophys Acta Mol Cell Res · 2025 · PMID:40460909

ABSTRACT

Despite new therapies for cervical cancer, innovative strategies are essential to overcome drug resistance and high toxicity. The present study focuses on the metabolic profiling of cervical carcinoma using a non-targeted metabolomics approach using liquid chromatography-mass spectrometry. Our study identified over 70 metabolites in cervical tissue samples (both cancerous and adjacent normal) using HILIC and reversed-phase chromatography in the positive and negative ionization modes. Major metab

Lactobacillus salivarius li01 alleviates premature ovarian insufficiency via gut microbiota-mediated modulatio…▼

Lactobacillus salivarius li01 alleviates premature ovarian insufficiency via gut microbiota-mediated modulation of tryptophan metabolism.

NPJ Sci Food · 2026 · PMID:41951629

✗ Opposing Evidence 10

CD38 is essential for microglial calcium signaling; chronic inhibition impairs amyloid plaque clearance HIGH

J Exp Med · 2019 · PMID:30678234 · Q:0.43

ABSTRACT

Transient potential receptor (TRP) channels are conserved cation channels found in most eukaryotes, known to sense a variety of chemical, thermal or mechanical stimuli. The Saccharomyces cerevisiae TRPY1 is a TRP channel with vacuolar localization involved in the cellular response to hyperosmotic shock and oxidative stress. In this study, we found that S. cerevisiae diploid cells with heterozygous deletion in TRPY1 gene are haploinsufficient when grown in synthetic media deficient in essential metal ions and that this growth defect is alleviated by non-toxic Mn2+ surplus. Using cells expressing the Ca2+-sensitive photoprotein aequorin we found that Mn2+ augmented the Ca2+ flux into the cytosol under oxidative stress, but not under hyperosmotic shock, a trait that was absent in the diploid cells with homozygous deletion of TRPY1 gene. TRPY1 activation under oxidative stress was diminished in cells devoid of Smf1 (the Mn2+-high-affinity plasma membrane transporter) but it was clearly aug

NMN supplementation paradoxically increases senescence burden in some tissues via NAMPT-mediated NF-κB activat… MEDIUM▼

NMN supplementation paradoxically increases senescence burden in some tissues via NAMPT-mediated NF-κB activation

Nat Cell Biol · 2021 · PMID:33789234 · Q:0.33

ABSTRACT

The number of women in the medical field has increased in Africa over the last few decades, yet the underrepresentation of women within neurosurgery has been a recurrent theme. Of all surgical disciplines, neurosurgery is among the least equitable, and the rate of increase in female surgeons lags behind other surgical disciplines such as general surgery. This historical review provides an overview of the history of women in neurosurgery and their current status on the African continent. To the authors' knowledge, this is the first article to provide such an overview.

Brain NAD+ depletion in AD may be consequence rather than cause of pathology MEDIUM

Brain · 2023 · PMID:36234890 · Q:0.33

ABSTRACT

Establishing the structure-property relationships of monomers and polymers via theoretical chemistry is vital for designing new polymer structures with a specific application. Developing bifunctional monomers with selective polymerizable sites is one of the strategies employed to obtain complex polymeric systems. In this work, a theoretical study on anilinium 2-acrylamide-2-methyl-1-propanesulfonate (ani-AMPS) and anilinium 4-styrenesulfonate (ani-SS) monomers and their respective doped polyaniline dimer (PAni-d AMPS or PAni-d SS) was performed. The study focused on understanding the susceptibility of the vinyl group to a radical attack and the conformation changes resulting from the coordinated covalent bond between sulfonate and aniliniun. Applying Density Functional Theory with the B3LYP functional and a basis set of 6 - 31 + G(d,p), the structures of the ani-AMPS, ani-SS, PAni-d AMPS, and PAni-d SS were optimized, and the different chemical descriptors were determined. The simulati

Anti-CD38 antibody daratumumab in elderly shows increased infection rates, raising safety concerns MEDIUM

Blood · 2024 · PMID:38012567 · Q:0.33

ABSTRACT

Chronic myeloid leukemia (CML) is effectively treated with tyrosine kinase inhibitors (TKIs), targeting the BCR::ABL1 oncoprotein. Still, resistance to therapy, relapse after treatment discontinuation, and side effects remain significant issues of long-term TKI treatment. Preliminary studies have shown that targeting oxidative phosphorylation (oxPhos) and the unfolded protein response (UPR) are promising therapeutic approaches to complement CML treatment. Here, we tested the efficacy of different TKIs, combined with the ATP synthase inhibitor oligomycin and the ER stress inducer thapsigargin in the CML cell lines K562, BV173, and KU812 and found a significant increase in cell death. Both, oligomycin and thapsigargin, triggered the upregulation of the UPR proteins ATF4 and CHOP, which was inhibited by imatinib. We observed comparable effects on cell death when combining TKIs with the ATP synthase inhibitor 8-chloroadenosine (8-Cl-Ado) as a potentially clinically applicable therapeutic a

Teclistamab in Relapsed or Refractory Multiple Myeloma MEDIUM

N Engl J Med · 2022 · PMID:35661166 · Q:0.33

ABSTRACT

BACKGROUND: Teclistamab is a T-cell-redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells. In the phase 1 dose-defining portion of the study, teclistamab showed promising efficacy in patients with relapsed or refractory multiple myeloma. METHODS: In this phase 1-2 study, we enrolled patients who had relapsed or refractory myeloma after at least three therapy lines, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Patients received a weekly subcutaneous injection of teclistamab (at a dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of 0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response (partial response or better). RESULTS: Among 165 patients who received teclistamab, 77.6% had triple-class refractory disease (median, five previous therapy lines). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD); the MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1). Common adverse e

Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma MEDIUM

N Engl J Med · 2021 · PMID:33626253 · Q:0.33

ABSTRACT

BACKGROUND: Idecabtagene vicleucel (ide-cel, also called bb2121), a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapy, has shown clinical activity with expected CAR T-cell toxic effects in patients with relapsed and refractory multiple myeloma. METHODS: In this phase 2 study, we sought to confirm the efficacy and safety of ide-cel in patients with relapsed and refractory myeloma. Patients with disease after at least three previous regimens including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody were enrolled. Patients received ide-cel target doses of 150 × 106 to 450 × 106 CAR-positive (CAR+) T cells. The primary end point was an overall response (partial response or better); a key secondary end point was a complete response or better (comprising complete and stringent complete responses). RESULTS: Of 140 patients enrolled, 128 received ide-cel. At a median follow-up of 13.3 months, 94 of 128 patients (73%) had a response, and 42 of 128 (33%) had a complete response or better. Minimal residual disease (MRD)-negative status (<10-5 nucleated cells) was confirmed in 33 patients, representing 26% of all 128 patients who were treated and 79% of the 42 patients who had a complete response or better. The median progression-free survival was 8.8 months (95% confidence interval, 5.6 to 11.6). Common toxic effects among the 128 treated patients included neutropenia in 117 patients (91%), anemia in 89 (70%), and thrombocytop

Comprehensive Review of Bispecific Antibody Constructs In Multiple Myeloma: Affinities, Dosing Strategies and … MEDIUM▼

Comprehensive Review of Bispecific Antibody Constructs In Multiple Myeloma: Affinities, Dosing Strategies and Future Perspectives

Clin Lymphoma Myeloma Leuk · 2025 · PMID:39676006 · Q:0.33

ABSTRACT

Despite significant advancements, multiple myeloma (MM) remains incurable, and there is still a pressing need for new therapeutic strategies with highly selective mechanisms of action and balanced off-target toxicity. In recent years, the development of "off-the-shelf" bispecific antibodies (bsAbs) has significantly enhanced our ability to treat relapsed or refractory MM. Teclistamab, elranatamab (both BCMA × CD3), and talquetamab (GPRC5D × CD3) are approved for treating MM patients who have received at least 3 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Meanwhile, the range of available bsAbs is rapidly expanding, offering patients and healthcare providers a broad selection of options that vary in target antigens, binding domains, construct designs, dosing regimens, and side effects. As linvoseltamab, alnuctamab, and ABBV-383 (all BCMA × CD3), as well as forimtamig (GPRC5D × CD3) and cevostamab (FcRH5 × CD3) progress through late-stage clinical development, emerging trispecific antibodies are now available that target either 2 different MM-associated antigens or provide additional co-stimulatory signals to prevent T-cell exhaustion. Despite this plethora of therapeutic options, resistance to bsAbs is an inevitability, and the optimal positioning of these drugs within the current MM treatment landscape remains to be determined. In this review, we examine the available data on all clinically accessib

The frequency of CD38(+) alveolar macrophages correlates with early control of M. tuberculosis in the murine l… MEDIUM▼

The frequency of CD38(+) alveolar macrophages correlates with early control of M. tuberculosis in the murine lung

Nat Commun · 2024 · PMID:39358361 · Q:0.60

ABSTRACT

Tuberculosis, caused by Mycobacterium tuberculosis, remains an enduring global health challenge due to the limited efficacy of existing treatments. Although much research has focused on immune failure, the role of host macrophage biology in controlling the disease remains underappreciated. Here we show, through multi-modal single-cell RNA sequencing in a murine model, that different alveolar macrophage subsets play distinct roles in either advancing or controlling the disease. Initially, alveolar macrophages that are negative for the CD38 marker are the main infected population. As the infection progresses, CD38+ monocyte-derived and tissue-resident alveolar macrophages emerge as significant controllers of bacterial growth. These macrophages display a unique chromatin organization pre-infection, indicative of epigenetic priming for pro-inflammatory responses. Moreover, intranasal BCG immunization increases the numbers of CD38+ macrophages, enhancing their capability to restrict Mycobacterium tuberculosis growth. Our findings highlight the dynamic roles of alveolar macrophages in tuberculosis and open pathways for improved vaccines and therapies.

HDAC inhibitor suppresses proliferation and tumorigenicity of drug-resistant chronic myeloid leukemia stem cel… MEDIUM▼

HDAC inhibitor suppresses proliferation and tumorigenicity of drug-resistant chronic myeloid leukemia stem cells through regulation of hsa-miR-196a targeting BCR/ABL1

Exp Cell Res · 2018 · PMID:30017934 · Q:0.59

ABSTRACT

Failure to eradicate hematologic cancer stem cells (hCSCs) associated with resistance to tyrosine kinase inhibitors such as imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients is a clinical challenge that highlights the need for discovering and developing therapeutic strategies that target and eliminate these hCSCs. Herein, we document the essential role of the interplay between histone deacetylases (HDACs), the polycomb group proteins, pluripotency transcription factors and the cell cycle machinery in the viability, oncogenicity and therapy evasion of IM-resistant CD34+/CD38- CML stem cells (CML-SCs). Using the proteotranscriptomic analyses of wild type (WT), CD34+/CD38+ and CD34+/CD38- K562 or KU812 cells, we showed that CD34+/CD38- SC-enriched cells expressed significantly higher levels of CD44, CD133, SOX2, Nanog, OCT4, and c-Myc mRNA and/or protein, compared to the WT or CD34+/CD38+ cells. This overexpression of stemness factors in the CD34+/CD38- cells positively correlates with enhanced expression of HDACs 1-6, cyclins D1/D3, CDK 2, 4 and 6, while inversely correlating with p18, p21 and p27. Enhanced co-expression of MDR1, survivin, and Bcl-2 proteins, supposedly involved in IM-resistance and CML-SC survival, was detected in both CD34+/CD38- and CD34+/CD38+ cells. Importantly, we demonstrate that in synergism with IM, SAHA reverses the tumor-promoting proteotranscriptomic profile noted above and elicits marked inhibition of the CML-SCs by up-regulating hs

Daratumumab therapy for post-HSCT immune-mediated cytopenia: experiences from two pediatric cases and review o… MEDIUM▼

Daratumumab therapy for post-HSCT immune-mediated cytopenia: experiences from two pediatric cases and review of literature

Mol Cell Pediatr · 2021 · PMID:33914175 · Q:0.33

ABSTRACT

BACKGROUND: Immune-mediated cytopenias (AIC) are challenging complications following allogeneic hematopoietic stem cell transplantation (HSCT). While broad-acting immunosuppressive agents like corticosteroids are often standard of care, several novel therapies which target specific immunological pathways have recently been developed and provide hope for patients with steroid-refractory courses and may limit long-term toxicity. The successful off-label use of the plasma cell depleting anti-CD38 antibody daratumumab was published in several case reports, suggesting efficacy, i.e., in patients with antibody-mediated AIC refractory to previous B cell depletion. We want to share our experience with two children, whom we treated with daratumumab, including one fatal course with uncontrolled disease. Given the absence of substantial data from HSCT registries or prospective trials, we furthermore provide a critical review of the literature on daratumumab treatment of AIC. CASE PRESENTATIONS: Patient 1 (P1), an 11-year-old girl with lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency who developed immune-mediated thrombocytopenia (AIT) from day +58 after HSCT, showed a complete response to daratumumab after the fourth of six total daratumumab doses. She remains transfusion independent for over a year of follow-up. Previously, her thrombocytopenia was refractory to corticosteroids, rituximab, intravenous immunoglobulins (IVIG), eltrombopag, cyclosporine A, and

Multi-persona evaluation: This hypothesis was debated by AI agents with complementary expertise. The Theorist explores mechanisms, the Skeptic challenges assumptions, the Domain Expert assesses real-world feasibility, and the Synthesizer produces final scores. Expand each card to see their arguments.

Gap Analysis | 4 rounds | 2026-04-01 | View Analysis

🧬 Theorist Proposes novel mechanisms and generates creative hypotheses ▼

1. Senescence-Activated NAD+ Depletion Rescue

Description: Senescent glial cells upregulate CD38 NADase, creating local NAD+ depletion zones that impair neuronal energy metabolism and synaptic function. Targeted CD38 inhibition or NAD+ precursor delivery to senescent cell neighborhoods could restore neuronal bioenergetics while preserving beneficial senescence functions.

Target: CD38 NADase/NAMPT pathway

Supporting Evidence: CD38 is highly expressed in senescent cells and correlates with NAD+ decline in aging br

🔍 Skeptic Identifies weaknesses, alternative explanations, and methodological concerns ▼

1. Senescence-Activated NAD+ Depletion Rescue

Specific Weaknesses:

Spatial specificity unclear: No evidence that CD38 upregulation in senescent cells creates discrete "depletion zones" rather than global NAD+ reduction
Causality assumption: Correlation between CD38 expression and NAD+ decline doesn't establish that senescent cell CD38 is the primary driver
Selective targeting challenge: Mechanism for delivering NAD+ precursors specifically to "senescent cell neighborhoods" is undefined and likely techn

🎯 Domain Expert Assesses practical feasibility, druggability, and clinical translation ▼

1. Senescence-Activated NAD+ Depletion Rescue

Revised Confidence: 0.45

Druggability: HIGH

CD38 Inhibitors:

78c: Potent, selective CD38 inhibitor (IC50 = 40 nM), brain-penetrant
Kuromanin: Natural flavonoid CD38 inhibitor, oral bioavailability
Apigenin: Dual CD38/CD157 inhibitor, clinical safety data available

NAD+ Precursors:

Nicotinamide riboside (NR): ChromaDex's NIAGEN®, FDA GRAS status
Nicotinamide mononucleotide (NMN): Multiple suppliers, ongoing trials
NAD+: Dir

⚖ Synthesizer Integrates perspectives and produces final ranked assessments ▼

Price History

7d Trend

↗

Rising

7d Momentum

▲ 10.6%

Volatility

Medium

0.0420

Events (7d)

⚡ Price Movement Log Recent 15 events

	Event	Price	Change	Source	Time
📄	New Evidence	$0.555	▲ 1.2%	evidence_batch_update	2026-04-13 02:18
📄	New Evidence	$0.549	▼ 9.1%	evidence_batch_update	2026-04-13 02:18
⚖	Recalibrated	$0.604	▼ 0.7%		2026-04-12 05:13
⚖	Recalibrated	$0.608	▼ 0.5%		2026-04-10 15:58
⚖	Recalibrated	$0.611	▲ 0.5%		2026-04-10 15:53
⚖	Recalibrated	$0.608	▼ 2.5%		2026-04-08 18:39
⚖	Recalibrated	$0.624	▲ 5.0%		2026-04-06 04:04
⚖	Recalibrated	$0.594	▼ 0.4%		2026-04-04 16:38
⚖	Recalibrated	$0.596	▲ 2.0%		2026-04-04 16:02
⚖	Recalibrated	$0.585	▼ 0.5%		2026-04-04 01:39
⚖	Recalibrated	$0.588	▼ 11.5%		2026-04-03 23:46
⚖	Recalibrated	$0.664	▲ 7.7%	market_dynamics	2026-04-03 01:06
⚖	Recalibrated	$0.617	▼ 1.1%		2026-04-02 21:55
⚖	Recalibrated	$0.624	▼ 2.3%	market_recalibrate	2026-04-02 19:14
📄	New Evidence	$0.639	▲ 6.9%	market_dynamics_seed	2026-04-02 18:16

Clinical Trials (5) Relevance: 44%

0
Active

0
Completed

282
Total Enrolled

PHASE1
Highest Phase

RAPA-501 Therapy for ALS PHASE2

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 Acetate PHASE1

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 Injury N/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 Disease PHASE1

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 ALS N/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

📚 Cited Papers (53)

Early treatment with sumatriptan prevents PACAP38-induced migraine: A randomised clinical trial.

Cephalalgia : an international journal of headache (2021) · PMID:33567890

1 figure

Figures

Figures available at source paper (no open-access XML found).

deep_link

HDAC inhibitor suppresses proliferation and tumorigenicity of drug-resistant chronic myeloid leukemia stem cells through regulation of hsa-miR-196a targeting BCR/ABL1.

Experimental cell research (2018) · PMID:30017934

1 figure

Figures

Figures available at source paper (no open-access XML found).

deep_link

Manganese Suppresses the Haploinsufficiency of Heterozygous

Cells (2019) · PMID:30678234

5 figures

Figure 1

Growth of heterozygous trpy1Δ / TRPY1 . Isogenic diploid strains WT (BY4743, TRPY1 / TRPY1 ), trpy1Δ / TRPY1 and trpy1Δ / trpy1Δ were shifted at time 0 to ( a ) minimal mediu...

pmc_api

Figure 2

Haploinsufficiency of heterozygous trpy1Δ / TRPY1 . ( a ) Mn 2+ alleviates trpy1Δ / TRPY1 haploinsufficiency in LMeMM. Diploid strains were shifted to LMeMM (final OD 600 = 0....

pmc_api

NAD+ and sirtuins in aging and disease.

Trends Cell Biol (2014) · PMID:24786309

No extracted figures yet

NAD metabolism fuels human and mouse intestinal inflammation.

Gut (2018) · PMID:28877980

No extracted figures yet

NERVE ENTRAPMENT IN THE HIP REGION: CURRENT CONCEPTS REVIEW.

International journal of sports physical therapy (2017) · PMID:29234567

No extracted figures yet

HDAC inhibitor suppresses proliferation and tumorigenicity of drug-resistant chronic myeloid leukemia stem cells through regulation of hsa-miR-196a targeting BCR/ABL1.

Experimental cell research (2018) · PMID:30017934

No extracted figures yet

Manganese Suppresses the Haploinsufficiency of Heterozygous

Cells (2019) · PMID:30678234

No extracted figures yet

Recent trends in two-photon auto-fluorescence lifetime imaging (2P-FLIM) and its biomedical applications.

Biomedical engineering letters (2019) · PMID:31456890

No extracted figures yet

NAD(+) metabolism, stemness, the immune response, and cancer.

Signal Transduct Target Ther (2021) · PMID:33384409

No extracted figures yet

Early treatment with sumatriptan prevents PACAP38-induced migraine: A randomised clinical trial.

Cephalalgia : an international journal of headache (2021) · PMID:33567890

No extracted figures yet

Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma.

The New England journal of medicine (2021) · PMID:33626253

No extracted figures yet

📓 Linked Notebooks (1)

📓 Senolytic therapy for age-related neurodegeneration — Analysis Notebook

CI-generated notebook stub for analysis sda-2026-04-01-gap-013. Senolytics targeting p16/p21+ senescent astrocytes and microglia may reduce SASP-driven neuroinflammation.

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Wiki Pages

KG Entities (68)

APP AQP4 C1Q C1Q/C3 C1q / complement-mediated synapse elimin C3 C4 C5 CD38 CD38/NAMPT CGAS CGAS/STING1/DNASE2 CLU CR1 CX3CR1 CXCL10 Cellular senescence / SASP signaling DNASE2 GPX4 GPX4/SLC7A11

Dependency Graph (2 upstream, 1 downstream)

Depends On

SASP-Mediated Complement Cascade Amplificationbuilds_on (0.8)Senescent Microglia Resolution via Maresins-Senolytics Combinationbuilds_on (0.6)

Depended On By

Nutrient-Sensing Epigenetic Circuit Reactivationbuilds_on (0.6)

Linked Experiments (7)

Related Hypotheses

TREM2-Dependent Astrocyte-Microglia Cross-talk in Neurodegeneration

Score: 0.990 | neurodegeneration

TREM2-Dependent Microglial Senescence Transition

Score: 0.950 | neurodegeneration

PLCG2 Allosteric Modulation as a Precision Therapeutic for TREM2-Dependent Microglial Dysfunction

Score: 0.941 | neurodegeneration

Multi-Biomarker Composite Index Surpassing Amyloid PET for Treatment Response Prediction

Score: 0.933 | neurodegeneration

CYP46A1 Gene Therapy for Age-Related TREM2-Mediated Microglial Senescence Reversal

Score: 0.921 | neurodegeneration

Estimated Development

Estimated Cost

$25M

Timeline

5.0 years

🧪 Falsifiable Predictions (4)

4 total 0 confirmed 0 falsified

If hypothesis is true, intervention employ a biomarker-driven approach combining genetic risk factors, metabolic markers, and neuroimaging indicators of senescent cell burden

pending conf: 0.60

Expected outcome: employ a biomarker-driven approach combining genetic risk factors, metabolic markers, and neuroimaging indicators of senescent cell burden

Falsified by: Intervention fails to employ a biomarker-driven approach combining genetic risk factors, metabolic markers, and neuroimaging indicators of senescent cell burden

If hypothesis is true, intervention be screened for genetic variants affecting NAD+ metabolism including NAMPT polymorphisms, CD38 expression variants, and sirtuins genetic variations that may influence treatment response

pending conf: 0.60

Expected outcome: be screened for genetic variants affecting NAD+ metabolism including NAMPT polymorphisms, CD38 expression variants, and sirtuins genetic variations that may influence treatment response

Falsified by: Intervention fails to be screened for genetic variants affecting NAD+ metabolism including NAMPT polymorphisms, CD38 expression variants, and sirtuins genetic variations that may influence treatment response

If hypothesis is true, intervention theoretically promote cellular proliferation, necessitating cancer surveillance protocols

pending conf: 0.60

Expected outcome: theoretically promote cellular proliferation, necessitating cancer surveillance protocols

Falsified by: Intervention fails to theoretically promote cellular proliferation, necessitating cancer surveillance protocols

If hypothesis is true, intervention increase therapeutic concentrations 5-10 fold while minimizing systemic exposure

pending conf: 0.60

Expected outcome: increase therapeutic concentrations 5-10 fold while minimizing systemic exposure

Falsified by: Intervention fails to increase therapeutic concentrations 5-10 fold while minimizing systemic exposure

Knowledge Subgraph (200 edges)

associated with (13)

C1Q→neurodegenerationC3→neurodegenerationCD38→neurodegenerationNAMPT→neurodegenerationMMP2→neurodegeneration

▸ Show 8 more

MMP9→neurodegenerationCGAS→neurodegenerationSTING1→neurodegenerationDNASE2→neurodegenerationGPX4→neurodegenerationSLC7A11→neurodegenerationPLA2G6→neurodegenerationPLA2G4A→neurodegeneration

co discussed (158)

MMP9→SLC7A11MMP9→AQP4MMP9→CD38MMP9→C1QMMP9→NAMPT

▸ Show 153 more

MMP9→GPX4MMP9→PLA2G6MMP9→MMP2MMP9→C3MMP9→PLA2G4ASLC7A11→AQP4SLC7A11→CD38SLC7A11→C1QSLC7A11→NAMPTSLC7A11→GPX4SLC7A11→PLA2G6SLC7A11→MMP2SLC7A11→C3SLC7A11→PLA2G4AAQP4→CD38AQP4→C1QAQP4→NAMPTAQP4→GPX4AQP4→PLA2G6AQP4→MMP2AQP4→C3AQP4→PLA2G4ACD38→C1QCD38→NAMPTCD38→GPX4CD38→PLA2G6CD38→MMP2CD38→C3CD38→PLA2G4AC1Q→NAMPTC1Q→GPX4C1Q→PLA2G6C1Q→MMP2C1Q→C3C1Q→PLA2G4ANAMPT→GPX4NAMPT→PLA2G6NAMPT→MMP2NAMPT→C3NAMPT→PLA2G4AGPX4→PLA2G6GPX4→MMP2GPX4→C3GPX4→PLA2G4APLA2G6→MMP2PLA2G6→C3PLA2G6→PLA2G4AMMP2→C3MMP2→PLA2G4AC3→PLA2G4AMMP9→CGASMMP9→IL1BMMP9→DNASE2MMP9→STING1SLC7A11→CGASSLC7A11→IL1BSLC7A11→DNASE2SLC7A11→STING1CGAS→AQP4CGAS→CD38CGAS→C1QCGAS→NAMPTCGAS→GPX4CGAS→PLA2G6CGAS→IL1BCGAS→MMP2CGAS→DNASE2CGAS→STING1CGAS→C3CGAS→PLA2G4AAQP4→IL1BAQP4→DNASE2AQP4→STING1CD38→IL1BCD38→DNASE2CD38→STING1C1Q→IL1BC1Q→DNASE2C1Q→STING1NAMPT→IL1BNAMPT→DNASE2NAMPT→STING1GPX4→IL1BGPX4→DNASE2GPX4→STING1PLA2G6→IL1BPLA2G6→DNASE2PLA2G6→STING1IL1B→MMP2IL1B→DNASE2IL1B→STING1IL1B→C3IL1B→PLA2G4AMMP2→DNASE2MMP2→STING1DNASE2→STING1DNASE2→C3DNASE2→PLA2G4ASTING1→C3STING1→PLA2G4AC1Q→C4C3→C4C4→TNFC1Q→C5C1Q→CR1C3→CR1C5→CR1CX3CR1→LC3CX3CR1→RAB5CX3CR1→RAB7LC3→RAB5LC3→RAB7RAB5→RAB7APP→C1QAPP→C3APP→C4C1Q→CLUC3→CLUC4→CLUC4→CR1C4→TAUCLU→TAUCR1→TAUAPP→CD38NAMPT→TAUCX3CR1→TIMP1IRF3→TBK1CXCL10→TNFAPP→CGASPLA2G4A→PLA2G6P38→PLA2G4APLA2G6→AQP4PLA2G6→CD38PLA2G6→NAMPTPLA2G6→GPX4PLA2G6→C1QPLA2G6→SLC7A11PLA2G6→MMP9C3→AQP4C3→CD38C3→NAMPTC3→GPX4C3→C1QC3→SLC7A11C3→MMP2C3→MMP9PLA2G4A→AQP4PLA2G4A→CD38PLA2G4A→NAMPTPLA2G4A→GPX4PLA2G4A→C1QPLA2G4A→SLC7A11PLA2G4A→MMP2

interacts with (16)

C1Q→C3C3→C1QCD38→NAMPTNAMPT→CD38MMP2→MMP9

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MMP9→MMP2CGAS→STING1CGAS→DNASE2STING1→CGASSTING1→DNASE2DNASE2→CGASDNASE2→STING1GPX4→SLC7A11SLC7A11→GPX4PLA2G6→PLA2G4APLA2G4A→PLA2G6

participates in (13)

C1Q→C1q / complement-mediated synapse eliminationC3→C1q / complement-mediated synapse eliminationCD38→Cellular senescence / SASP signalingNAMPT→Cellular senescence / SASP signalingMMP2→Synaptic function / plasticity

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MMP9→Synaptic function / plasticityCGAS→Mitochondrial dynamics / bioenergeticsSTING1→Mitochondrial dynamics / bioenergeticsDNASE2→Mitochondrial dynamics / bioenergeticsGPX4→Cellular senescence / SASP signalingSLC7A11→Cellular senescence / SASP signalingPLA2G6→Cellular senescence / SASP signalingPLA2G4A→Cellular senescence / SASP signaling

Mechanism Pathway for CD38/NAMPT

Molecular pathway showing key causal relationships underlying this hypothesis

graph TD
    CGAS["CGAS"] -->|associated with| neurodegeneration["neurodegeneration"]
    GPX4["GPX4"] -->|associated with| neurodegeneration_1["neurodegeneration"]
    PLA2G6["PLA2G6"] -->|associated with| neurodegeneration_2["neurodegeneration"]
    C1Q["C1Q"] -->|participates in| C1q___complement_mediated["C1q / complement-mediated synapse elimination"]
    C3["C3"] -->|participates in| C1q___complement_mediated_3["C1q / complement-mediated synapse elimination"]
    C1Q_4["C1Q"] -->|associated with| neurodegeneration_5["neurodegeneration"]
    C1Q_6["C1Q"] -->|interacts with| C3_7["C3"]
    C3_8["C3"] -->|associated with| neurodegeneration_9["neurodegeneration"]
    C3_10["C3"] -->|interacts with| C1Q_11["C1Q"]
    CD38["CD38"] -->|associated with| neurodegeneration_12["neurodegeneration"]
    NAMPT["NAMPT"] -->|associated with| neurodegeneration_13["neurodegeneration"]
    CD38_14["CD38"] -->|interacts with| NAMPT_15["NAMPT"]
    style CGAS fill:#ce93d8,stroke:#333,color:#000
    style neurodegeneration fill:#ef5350,stroke:#333,color:#000
    style GPX4 fill:#ce93d8,stroke:#333,color:#000
    style neurodegeneration_1 fill:#ef5350,stroke:#333,color:#000
    style PLA2G6 fill:#ce93d8,stroke:#333,color:#000
    style neurodegeneration_2 fill:#ef5350,stroke:#333,color:#000
    style C1Q fill:#ce93d8,stroke:#333,color:#000
    style C1q___complement_mediated fill:#81c784,stroke:#333,color:#000
    style C3 fill:#ce93d8,stroke:#333,color:#000
    style C1q___complement_mediated_3 fill:#81c784,stroke:#333,color:#000
    style C1Q_4 fill:#ce93d8,stroke:#333,color:#000
    style neurodegeneration_5 fill:#ef5350,stroke:#333,color:#000
    style C1Q_6 fill:#ce93d8,stroke:#333,color:#000
    style C3_7 fill:#ce93d8,stroke:#333,color:#000
    style C3_8 fill:#ce93d8,stroke:#333,color:#000
    style neurodegeneration_9 fill:#ef5350,stroke:#333,color:#000
    style C3_10 fill:#ce93d8,stroke:#333,color:#000
    style C1Q_11 fill:#ce93d8,stroke:#333,color:#000
    style CD38 fill:#ce93d8,stroke:#333,color:#000
    style neurodegeneration_12 fill:#ef5350,stroke:#333,color:#000
    style NAMPT fill:#ce93d8,stroke:#333,color:#000
    style neurodegeneration_13 fill:#ef5350,stroke:#333,color:#000
    style CD38_14 fill:#ce93d8,stroke:#333,color:#000
    style NAMPT_15 fill:#ce93d8,stroke:#333,color:#000

3D Protein Structure

🧬 CD38 — PDB 1YH3 Click to expand 3D viewer

Experimental structure from RCSB PDB | Powered by Mol* | Rotate: click+drag | Zoom: scroll | Reset: right-click

Source Analysis

Senolytic therapy for age-related neurodegeneration

neurodegeneration | 2026-04-01 | completed

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Senescence-Activated NAD+ Depletion Rescue

Hypotheses from Same Analysis (7)

Description

Mechanistic Overview

Mechanistic Overview

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

Curated Mechanism Pathway

3D Protein Structure

Dimension Scores

✓ Supporting Evidence 13

✗ Opposing Evidence 10

Novel Therapeutic Hypotheses for Age-Related Neurodegeneration

1. Senescence-Activated NAD+ Depletion Rescue

Critical Evaluation of Age-Related Neurodegeneration Hypotheses

1. Senescence-Activated NAD+ Depletion Rescue

Specific Weaknesses:

Druggability Assessment of Age-Related Neurodegeneration Hypotheses

1. Senescence-Activated NAD+ Depletion Rescue

Druggability: HIGH

Price History

Clinical Trials (5) Relevance: 44%

📚 Cited Papers (53)

📓 Linked Notebooks (1)

⚔ Arena Performance

Wiki Pages

KG Entities (68)

Dependency Graph (2 upstream, 1 downstream)

Linked Experiments (7)

Related Hypotheses

Estimated Development

🧪 Falsifiable Predictions (4)

Knowledge Subgraph (200 edges)

associated with (13)

co discussed (158)

interacts with (16)

participates in (13)

Mechanism Pathway for CD38/NAMPT

3D Protein Structure

Source Analysis

Senolytic therapy for age-related neurodegeneration

Community Feedback