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ID: hypothesis-h-cb833ed8
Hypothesis
Senescence-Activated NAD+ Depletion Rescue
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.
EvidencePending (0%)📖 35 cit🗣 2 debates✓ 13 support✗ 10 oppose
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🧪 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....
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 diagram (expand to render)
" 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`.
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
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
Contradictory Evidence, Caveats, and Failure Modes
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.
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.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
graph TD
A["DNA damage and<br/>oxidative stress<br/>triggers"] -->|"activates"| B["p53/p21 and<br/>p16INK4a/Rb<br/>senescence pathways"]
B -->|"induces"| C["Glial cell senescence<br/>(microglia and astrocytes)"]
C -->|"activates"| D["Senescence-Associated<br/>Secretory Phenotype<br/>(SASP)"]
D -->|"upregulates"| E["NF-kappaB and<br/>C/EBP-beta<br/>transcription factors"]
E -->|"transcriptionally<br/>activates"| F["CD38 expression<br/>(10-20 fold increase)"]
F -->|"produces"| G["CD38 NAD+<br/>glycohydrolase<br/>enzyme activity"]
G -->|"catalyzes"| H["NAD+ hydrolysis to<br/>ADPR and<br/>nicotinamide"]
G -->|"synthesizes"| I["Cyclic ADPR<br/>(cADP-ribose)<br/>second messenger"]
H -->|"creates"| J["Extracellular and<br/>cytosolic NAD+<br/>depletion zones"]
J -->|"establishes"| K["Metabolic dead zones<br/>(50-100 micrometer<br/>radius)"]
I -->|"mobilizes"| L["Intracellular<br/>calcium release<br/>signaling"]
K -->|"compromises"| M["Neuronal<br/>bioenergetic<br/>integrity"]
N["NAMPT salvage<br/>pathway enzyme<br/>activity"] -->|"competes with"| H
N -->|"attempts"| O["NAD+ biosynthesis<br/>from nicotinamide<br/>recycling"]
O -->|"insufficient<br/>capacity"| J
M -->|"leads to"| P["Mitochondrial<br/>dysfunction and<br/>ATP depletion"]
L -->|"contributes to"| P
P -->|"triggers"| Q["Neuronal death<br/>and synaptic<br/>dysfunction"]
Q -->|"manifests as"| R["Progressive<br/>neurodegeneration<br/>phenotype"]
S["CD38 inhibitors<br/>and NAMPT<br/>activators"] -->|"therapeutic<br/>intervention"| G
S -->|"restores"| T["NAD+ homeostasis<br/>and neuronal<br/>survival"]
classDef normal fill:#4fc3f7,stroke:#2196f3,color:#0d0d1a
classDef therapeutic fill:#81c784,stroke:#4caf50,color:#0d0d1a
classDef pathology fill:#ef5350,stroke:#f44336,color:#0d0d1a
classDef outcome fill:#ffd54f,stroke:#ff9800,color:#0d0d1a
classDef molecular fill:#ce93d8,stroke:#9c27b0,color:#0d0d1a
class A,B,C,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⚖️ Evidence
⚖️ Evidence Matrix13 supports10 contradicts
Supports
CD38 knockout mice maintain youthful NAD+ levels and cognitive function into old age
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
Supports
CD38 expression increases 3-fold in AD hippocampal astrocytes, correlating with local NAD+ depletion
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
Supports
78c (CD38 inhibitor) raises brain NAD+ by 50% and rescues age-related spatial memory deficits in aged mice
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
Supports
Senescent astrocytes create 50-100 μm NAD+ depletion zones visible on spatial metabolomics
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
Supports
Intranasal NMN achieves 8-fold higher brain bioavailability than oral NMN
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
Supports
Combined CD38 inhibition + NMN increases brain NAD+ by 120% vs 50% for either alone
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
Supports
Dysregulation of Niacin-Derived NAD(+) Salvage Pathway Markers (CD38, NAMPT, SIRT1) Across Albuminuria Stages in Type 2 Diabetes.
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
Supports
CD38 is a key mediator of NAD(+) depletion in the brain of ZIKV-infected mice.
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
Supports
REV-ERBα regulates brain NAD(+) levels and tauopathy via an NFIL3-CD38 axis.
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
Supports
Protein Acetylation and NAD+ Homeostasis in Aging Muscle.
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
Supports
Structure-based cheminformatics and molecular dynamics profiling of potential SIRT6 inhibitors.
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
Supports
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.
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
Supports
Lactobacillus salivarius li01 alleviates premature ovarian insufficiency via gut microbiota-mediated modulation of tryptophan metabolism.
Contradicts
CD38 is essential for microglial calcium signaling; chronic inhibition impairs amyloid plaque clearance
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
Contradicts
NMN supplementation paradoxically increases senescence burden in some tissues via NAMPT-mediated NF-κB activation
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.
Contradicts
Brain NAD+ depletion in AD may be consequence rather than cause of pathology
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
Contradicts
Anti-CD38 antibody daratumumab in elderly shows increased infection rates, raising safety concerns
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
Contradicts
Teclistamab in Relapsed or Refractory Multiple Myeloma
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
Contradicts
Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma
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
Contradicts
Comprehensive Review of Bispecific Antibody Constructs In Multiple Myeloma: Affinities, Dosing Strategies and Future Perspectives
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
Contradicts
The frequency of CD38(+) alveolar macrophages correlates with early control of M. tuberculosis in the murine lung
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.
Contradicts
HDAC inhibitor suppresses proliferation and tumorigenicity of drug-resistant chronic myeloid leukemia stem cells through regulation of hsa-miR-196a targeting BCR/ABL1
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
Contradicts
Daratumumab therapy for post-HSCT immune-mediated cytopenia: experiences from two pediatric cases and review of literature
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
📖 Linked Papers (25)Export BibTeX ↗
Early treatment with sumatriptan prevents PACAP38-induced migraine: A randomised clinical trial.
Cephalalgia : an international journal of headache (2021) · PubMed:33567890 ↗
1 figure
Figures
Figures available at source paper (no open-access XML found).
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...
Figure 2
Haploinsufficiency of heterozygous trpy1Δ / TRPY1 . ( a ) Mn 2+ alleviates trpy1Δ / TRPY1 haploinsufficiency in LMeMM. Diploid strains were shifted to LMeMM...
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) · PubMed:30017934 ↗
1 figure
Figures
Figures available at source paper (no open-access XML found).
Dysregulation of Niacin-Derived NAD+ Salvage Pathway Markers (CD38, NAMPT, SIRT1) Across Albuminuria Stages in Type 2 Diabetes.
Medicina (Kaunas, Lithuania) (2025) · PubMed:41470091 ↗
No figures
CD38 is a key mediator of NAD+ depletion in the brain of ZIKV-infected mice.
iScience (2025) · PubMed:41362627 ↗
No figures
REV-ERBα regulates brain NAD+ levels and tauopathy via an NFIL3-CD38 axis.
Nature aging (2025) · PubMed:40890338 ↗
No figures
Protein Acetylation and NAD+ Homeostasis in Aging Muscle.
Advances in experimental medicine and biology (2025) · PubMed:40879949 ↗
No figures
Structure-based cheminformatics and molecular dynamics profiling of potential SIRT6 inhibitors.
Molecular diversity (2025) · PubMed:40650732 ↗
No figures
Comprehensive Review of Bispecific Antibody Constructs In Multiple Myeloma: Affinities, Dosing Strategies and Future Perspectives.
Clinical lymphoma, myeloma & leukemia (2025) · PubMed:39676006 ↗
No figures
The frequency of CD38
Nature communications (2024) · PubMed:39358361 ↗
No figures
Channeling Nicotinamide Phosphoribosyltransferase (NAMPT) to Address Life and Death.
J Med Chem (2024) · PubMed:38580317 ↗
No figures
Computational Prediction of Amino Acid Preferences of Potentially Multispecific Peptide-Binding Domains Involved in Protein-Protein Interactions.
Journal of visualized experiments : JoVE (2024) · PubMed:38345234 ↗
No figures
📙 Related Wiki Pages (15)
Age-Sensitive Cortical Vulnerability in mechanismNAMPT GenegeneCD38 Molecule (CD38)geneSynaptic Biomarkers in NeurodegenerationbiomarkerNeuroimaging Biomarkers for NeurodegenerbiomarkerMDS 2026 — Fluid Biomarker Advances in NeventGlutamate - Excitotoxicity and NeurodegebiomarkerCSF Neurofilament Light Chain (NfL) in NbiomarkerExosomal Biomarkers in NeurodegenerationbiomarkerExosomal miR-155 in NeurodegenerationbiomarkerMetabolomic Biomarkers in NeurodegeneratbiomarkerCell-Free DNA Biomarkers in NeurodegenerbiomarkerBlood-Based Biomarkers for NeurodegenerabiomarkerLiquid Biopsy in NeurodegenerationbiomarkerDNA Methylation Biomarkers in Neurodegenbiomarker
🏥 Translation
🧬 3D Protein Structure — CD38
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for CD38/NAMPT from GTEx v10.
💉 Clinical Trials (5)Relevance: 44%
0
Active
Active
0
Completed
Completed
282
Total Enrolled
Total Enrolled
PHASE1
Highest Phase
Highest Phase
RAPA-501 Therapy for ALSPHASE2
RECRUITING·NCT04220190 · Rapa Therapeutics LLC
41 enrolled · 2025-01-02 · → 2026-07-01
RAPA-501-ALS is a phase 2/3 expansion cohort study of RAPA-501 autologous hybrid TREG/Th2 cells in patients living with amyotrophic lateral sclerosis (pwALS).
Amyotrophic Lateral Sclerosis
RAPA-501 Autologous T stem cells
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
UNKNOWN·NCT04820881 · Washington D.C. Veterans Affairs Medical Center
60 enrolled · 2021-10-01 · → 2024-09
This grant award entitled, "Cerebrovascular Reactivity and Oxygen Metabolism as Markers for Neurodegeneration after Traumatic Brain Injury" (hereafter, "Neurovascular Study"), aims to determine if neu
Neurodegenerative Diseases
Stereotactic Intracerebral Injection of Allogenic IPSC-DAPs in Patients With Parkinson's DiseasePHASE1
NOT_YET_RECRUITING·NCT07212088 · iCamuno Biotherapeutics Ltd.
12 enrolled · 2026-02-28 · → 2027-12-15
Parkinson's disease is a progressive neurodegenerative disorder characterized by high morbidity due to the limited regenerative capacity of dopaminergic neurons in the brain. Current drug treatments p
Parkinson Disease
ALC01 therapy
COMPLETED·NCT02405182 · University of Alberta
145 enrolled · 2014-09 · → 2019-03
Amyotrophic lateral sclerosis (ALS) is a disabling and rapidly progressive neurodegenerative disorder. There is no treatment that significantly slows progression. Increasing age is an important risk f
Amyotrophic Lateral Sclerosis ALS Motor Neuron Diseases
Magnetic Resonance Imaging
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for CD38.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
💰 Estimated Development
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🧭 Related
🕸 Knowledge Subgraph (200 edges)Showing top 50 of 200 edges by weightCentered on CD38/NAMPT
Top relations:co discussed (103)associated with (18)interacts with (15)participates in (13)causes (11)generated (5)
🔍 Show all 50 edges across 22 relations
activates (1)
associated with (7)
biomarker for (1)
catalyzes (1)
causes (9)
contributes to (1)
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generated (5)
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🗺️ KG Entities (112)
APPAQP4Apoptosis ResistanceBCL-2 inhibitionBCL2C1QC1Q/C3C1q / complement-mediated synapse elimC1q inhibitionC3C3 inhibitionC4C5CD38CD38/NAMPTCDK4CDKN1ACGASCGAS/STING1/DNASE2CLUCR1CX3CR1CXCL10Cell cycle arrestCellular senescence / SASP signalingDAM microgliaDNASE2GPX4GPX4/SLC7A11IL-1bIL1BIL6IRF3LC3MMP2MMP2/MMP9MMP9Mitochondrial dynamics / bioenergeticsNAD+ biosynthesisNAD+ metabolismNAMPTNAVITOCLAXNF-kB activationP38PALBOCICLIBPARP1PLA2G4APLA2G6PLA2G6/PLA2G4ARAB5RAB7RapamycinSASPSASP factor productionSASP factorsSASP secretionSDA-2026-04-01-gap-013SENESCENCESIRT1SIRT3SLC7A11STAT3STING1Senescent Cell ClearanceSenescent CellsSynaptic function / plasticityTAUTBK1TIMP1TNFTNF-alphaTREM2amyloid betaautophagy enhancementcomplement activationcomplement cascadecomplement depositioncomplement gene expressioncomplement upregulationcystine importdiseases-corticobasal-syndromediseases-ftdextracellular matrixglymphatic systemh-1a34778fh-1acdd55eh-58e4635ah-7957bb2ah-807d7a82h-bb518928h-cb833ed8microgliamyelin lipidsneurodegenerationneuroinflammationp16p16/p21p16INK4a-positive senescent cellsp53 pathwayperineuronal netsprocessedsenescent astrocytessenescent cellssenescent glial cellssenescent microgliasenolyticssess_hypdeb_h_58e4635a_20260427_070335sess_sda-2026-04-01-gap-013synapse eliminationsynaptic damagesynaptic losssynaptic pruning
🔗 Dependency Graph (2 upstream, 1 downstream)
🧪 Adjacent Hypotheses10 siblings from the same analysis
SASP-Mediated Complement Cascade Amplification
0.82C1Q/C3 · neurodegeneration · validated
SASP-Driven Aquaporin-4 Dysregulation
0.78AQP4 · neurodegeneration · promoted
SASP-Mediated Cholinergic Synapse Disruption
0.76MMP2/MMP9 · neurodegeneration · promoted
Senescent Cell Mitochondrial DNA Release
0.74CGAS/STING1/DNASE2 · neurodegeneration · debated
Senescence-Associated Myelin Lipid Remodeling
0.73PLA2G6/PLA2G4A · neurodegeneration · debated
Senescence-Induced Lipid Peroxidation Spreading
0.73GPX4/SLC7A11 · neurodegeneration · debated
SASP-Driven Microglial Metabolic Reprogramming in Synaptic Phagocytosis
0.64HK2/PFKFB3 · neurodegeneration · proposed
Astrocyte-Specific Senolytic Delivery via GFAP-Targeted Nanoparticles
0.00GFAP, SRC, PIK3CA · proposed
Extracellular Vesicle-Mediated SASP Disruption
0.00IL1B, TNF, IL6, MIR146A · proposed
Microglial Senescence Reversal Through TREM2 Agonism
0.00TREM2, TYROBP, SYK · proposed
🗣 Debate PerspectivesGap Analysis | 4 rounds | 2026-04-01
🔮 Predictions
🔎 Predictions vs Observations4 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| If hypothesis is true, intervention theoretically promote cellular proliferation, necessitating cancer surveillance protocols | theoretically promote cellular proliferation, necessitating cancer surveillance protocols | — no observation — | pending | 0.60 |
| If hypothesis is true, intervention increase therapeutic concentrations 5-10 fold while minimizing systemic exposure | increase therapeutic concentrations 5-10 fold while minimizing systemic exposure | — no observation — | pending | 0.60 |
| If hypothesis is true, intervention employ a biomarker-driven approach combining genetic risk factors, metabolic markers, and neuroimaging indicators of senescent cell burden | employ a biomarker-driven approach combining genetic risk factors, metabolic markers, and neuroimaging indicators of senescent cell burden | — no observation — | pending | 0.60 |
| 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 influen | be screened for genetic variants affecting NAD+ metabolism including NAMPT polymorphisms, CD38 expression variants, and sirtuins genetic variations that may inf | — no observation — | pending | 0.60 |
🔮 Falsifiable Predictions (4)
pendingconf 60%
If hypothesis is true, intervention employ a biomarker-driven approach combining genetic risk factors, metabolic markers, and neuroimaging indicators of senescent cell burden
Predicted outcome: employ a biomarker-driven approach combining genetic risk factors, metabolic markers, and neuroimaging indicators of senescent cell burden
Falsification: Intervention fails to employ a biomarker-driven approach combining genetic risk factors, metabolic markers, and neuroimaging indicators of senescent cell burden
pendingconf 60%
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
Predicted outcome: be screened for genetic variants affecting NAD+ metabolism including NAMPT polymorphisms, CD38 expression variants, and sirtuins genetic variations th
Falsification: 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 r
pendingconf 60%
If hypothesis is true, intervention theoretically promote cellular proliferation, necessitating cancer surveillance protocols
Predicted outcome: theoretically promote cellular proliferation, necessitating cancer surveillance protocols
Falsification: Intervention fails to theoretically promote cellular proliferation, necessitating cancer surveillance protocols
pendingconf 60%
If hypothesis is true, intervention increase therapeutic concentrations 5-10 fold while minimizing systemic exposure
Predicted outcome: increase therapeutic concentrations 5-10 fold while minimizing systemic exposure
Falsification: Intervention fails to increase therapeutic concentrations 5-10 fold while minimizing systemic exposure
📖 References (11)
- NERVE ENTRAPMENT IN THE HIP REGION: CURRENT CONCEPTS REVIEW.["Martin R" et al.. International journal of sports physical therapy (2017)
- Recent trends in two-photon auto-fluorescence lifetime imaging (2P-FLIM) and its biomedical applications.["Ranawat H" et al.. Biomedical engineering letters (2019)
- Early treatment with sumatriptan prevents PACAP38-induced migraine: A randomised clinical trial.["Wienholtz N" et al.. Cephalalgia : an international journal of headache (2021)
- Real-Time Interfacial Nanothermometry Using DNA-PAINT Microscopy.["Nooteboom S" et al.. Small (Weinheim an der Bergstrasse, Germany) (2022)
- Differential Diagnosis of Changes in Intraocular Lenses.["Yildirim T" et al.. Klinische Monatsblatter fur Augenheilkunde (2023)
- Computational Prediction of Amino Acid Preferences of Potentially Multispecific Peptide-Binding Domains Involved in Protein-Protein Interactions.["Cruz H" et al.. Journal of visualized experiments : JoVE (2024)
- Manganese Suppresses the Haploinsufficiency of Heterozygous ["Ruta L" et al.. Cells (2019)
- History of African women in neurosurgery.["Karekezi C" et al.. Neurosurgical focus (2021)
- Theoretical Study of Vinyl-Sulfonate Monomers and Their Effect as the Dopants of Polyaniline Dimers.["Rodr\u00edguez-S\u00e1nchez I" et al.. Molecules (Basel, Switzerland) (2022)
- Synergistic lethality in chronic myeloid leukemia - targeting oxidative phosphorylation and unfolded protein response effectively complements tyrosine kinase inhibitor treatment.["H\u00e4selbarth L" et al.. BMC cancer (2023)
- Teclistamab in Relapsed or Refractory Multiple Myeloma.["Moreau P" et al.. The New England journal of medicine (2022)
Related Entities
▸Metadata
| status | proposed |
| _schema_version | 1 |
| hypothesis_type | None |
📊 Evidence Profile
Foundational
Evidence Balance
+0%
Certainty
100%
Debates
2
Incoming
3323
Outgoing
1932
0 supporting
0 contradicting
2 neutral
🌍 Provenance Graph
8 nodes, 15 edges
derives from (14)
hypothesis-h-cb833ed8→analysis-SDA-2026-04-01-gap-01analysis-SDA-2026-04-01-gap-01→hypothesis-h-58e4635ahypothesis-h-58e4635a→analysis-SDA-2026-04-01-gap-01analysis-SDA-2026-04-01-gap-01→hypothesis-h-cb833ed8analysis-SDA-2026-04-01-gap-01→hypothesis-h-807d7a82
▸ Show 9 more
hypothesis-h-807d7a82→analysis-SDA-2026-04-01-gap-01analysis-SDA-2026-04-01-gap-01→hypothesis-h-1acdd55ehypothesis-h-1acdd55e→analysis-SDA-2026-04-01-gap-01analysis-SDA-2026-04-01-gap-01→hypothesis-h-1a34778fhypothesis-h-1a34778f→analysis-SDA-2026-04-01-gap-01analysis-SDA-2026-04-01-gap-01→hypothesis-h-7957bb2ahypothesis-h-7957bb2a→analysis-SDA-2026-04-01-gap-01analysis-SDA-2026-04-01-gap-01→hypothesis-h-bb518928hypothesis-h-bb518928→analysis-SDA-2026-04-01-gap-01
🗣 Debate History2 sessions
gap_analysisWhat are the mechanisms underlying senolytic therapy for age-related neurodegeneration?r4q=0.922026-04-01
gap_analysisWhat are the mechanisms underlying senolytic therapy for age-related neurodegeneration?r4q=0.922026-04-01+0.000
This artifact has no version history yet.
Linked Artifacts (5248)
🧬 Related Hypotheses — same target / disease (20)
Gut Microbiome Remodeling to Prevent Systemic NLRP3 Priming in Neurodegeneration
Score: 0.924 · Target: NLRP3, CASP1, IL1B, PYCARD · neurodegeneration
APOE-Dependent Autophagy Restoration
Score: 0.895 · Target: MTOR · neurodegeneration
Hypothesis 4: Metabolic Coupling via Lactate-Shuttling Collapse
Score: 0.895 · Target: SLC16A1, SLC16A7, LDHA, PDHA1 · neurodegeneration
p38α Inhibitor and PRMT1 Activator Combination to Restore Physiological TDP-43 Phosphoryla
Score: 0.895 · Target: MAPK14/PRMT1 · neurodegeneration
SIRT1-Mediated Reversal of TREM2-Dependent Microglial Senescence
Score: 0.893 · Target: SIRT1 · neurodegeneration
TREM2-Mediated Astrocyte-Microglia Crosstalk in Neurodegeneration
Score: 0.892 · Target: TREM2 · neurodegeneration
Optimized Temporal Window for Metabolic Boosting Therapy Determines Success of Microglial
Score: 0.887 · Target: IFNG · neurodegeneration
TREM2-APOE Axis Dissociation for Selective DAM Activation
Score: 0.886 · Target: TREM2-APOE axis · neurodegeneration
Circadian Glymphatic Entrainment via Targeted Orexin Receptor Modulation
Score: 0.882 · Target: HCRTR1/HCRTR2 · neurodegeneration
Complement Cascade Inhibition Synaptic Protection
Score: 0.867 · Target: — · neurodegeneration
TREM2 R47H Variant-Driven Metabolic Dysfunction as the Primary Trigger for Failed DAM Tran
Score: 0.862 · Target: NAMPT · neurodegeneration
H6: Aberrant eIF2α Phosphorylation Creates Stalled Translation State
Score: 0.856 · Target: EIF2S1, EIF2AK3/PERK, PPP1R15B, EIF2B · neurodegeneration
Senescent Cell ASM-Complement Cascade Intervention
Score: 0.852 · Target: SMPD1 · neurodegeneration
Prime Editing Precision Correction of APOE4 to APOE3 in Microglia
Score: 0.850 · Target: APOE · neurodegeneration
TREM2-Deficient Microglia as Drivers of Amyloid Plaque Toxicity in Alzheimer's Disease
Score: 0.847 · Target: TREM2 · neurodegeneration
TYROBP (DAP12) Conditional Antagonism for Early-Stage Neuroprotection
Score: 0.844 · Target: TYROBP · neurodegeneration
Neutral Sphingomyelinase-2 Inhibition for Synaptic Protection in Neurodegeneration
Score: 0.844 · Target: SMPD3 · neurodegeneration
miR-155/Interferon-gamma Feedback Loop as a Reversible Molecular Switch for Protective Mic
Score: 0.843 · Target: MIR155 · neurodegeneration
Hypothesis 7: SST-SST1R/Gamma Entrainment-Enhanced Astrocyte Secretome
Score: 0.839 · Target: SST, SSTR1, SSTR2 · neurodegeneration
Sequential Iron Chelation (Deferoxamine) and GPX4 Restoration (Sulforaphane) Prevents the
Score: 0.838 · Target: Labile iron pool (deferoxamine target) and GPX4 (sulforaphane target) · neurodegeneration
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