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During the COVID-19 pandemic, efforts have been made worldwide to develop effective therapies to address the devastating immune-mediated effects of SARS-CoV-2. With the exception of monoclonal antibody-mediated therapeutics and preventive approaches such as mass immunization, most experimental or repurposed drugs have failed in large randomized clinical trials (https://www.who.int/publications/i/item/therapeutics-and-covid-19-living-guideline). The worldwide spread of SARS-CoV-2 virus revealed specific susceptibilities to the virus among the elderly and individuals with age-related syndromes. These populations were more likely to experience a hyperimmune response characterized by a treatment-resistant acute lung pathology accompanied by multiple organ failure. These observations underscore the interplay between the virus, the biology of aging, and outcomes observed in the most severe cases of SARS-CoV-2 infection. The ectoenzyme CD38 has been implicated in the process of "inflammaging" in aged tissues. In a current publication, Horenstein et al. present evidence to support the hypothesis that CD38 plays a central role in altered immunometabolism resulting from COVID-19 infection. The authors discuss a critical but underappreciated trifecta of CD38-mediated NAD+ metabolism, aging, and COVID-19 immune response and speculate that the CD38/NAD+ axis is a promising therapeutic target for this disease.
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ADP-Ribosil Ciclase 1/metabolismo , COVID-19/fisiopatologia , Glicoproteínas de Membrana/metabolismo , SARS-CoV-2 , ADP-Ribosil Ciclase 1/genética , Envelhecimento , Regulação Enzimológica da Expressão Gênica , Humanos , Glicoproteínas de Membrana/genética , NAD/metabolismoRESUMO
This medical review addresses the hypothesis that CD38/NADase is at the center of a functional axis (i.e., intracellular Ca2+ mobilization/IFNγ response/reactive oxygen species burst) driven by severe acute respiratory syndrome coronavirus 2 infection, as already verified in respiratory syncytial virus pathology and CD38 activity in other cellular settings. Key features of the hypothesis are that 1) the substrates of CD38 (e.g., NAD+ and NADP+) are depleted by viral-induced metabolic changes; 2) the products of the enzymatic activity of CD38 [e.g., cyclic adenosine diphosphate-ribose (ADPR)/ADPR/nicotinic acid adenine dinucleotide phosphate] and related enzymes [e.g., poly(ADP-ribose)polymerase, Sirtuins, and ADP-ribosyl hydrolase] are involved in the anti-viral and proinflammatory response that favors the onset of lung immunopathology (e.g., cytokine storm and organ fibrosis); and 3) the pathological changes induced by this kinetic mechanism may be reduced by distinct modulators of the CD38/NAD+ axis (e.g., CD38 blockers, NAD+ suppliers, among others). This view is supported by arrays of associative basic and applied research data that are herein discussed and integrated with conclusions reported by others in the field of inflammatory, immune, tumor, and viral diseases.
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ADP-Ribosil Ciclase 1/metabolismo , COVID-19/metabolismo , Glicoproteínas de Membrana/metabolismo , SARS-CoV-2 , ADP-Ribosil Ciclase 1/genética , COVID-19/patologia , COVID-19/virologia , Regulação Enzimológica da Expressão Gênica , Humanos , Glicoproteínas de Membrana/genéticaRESUMO
PD1 blockade therapy, harnessing the cytotoxic potential of CD8+ T cells, has yielded clinical success in treating malignancies. However, its efficacy is often limited due to the progressive differentiation of intratumoral CD8+ T cells into a hypofunctional state known as terminal exhaustion. Despite identifying CD8+ T cell subsets associated with immunotherapy resistance, the molecular pathway triggering the resistance remains elusive. Given the clear association of CD38 with CD8+ T cell subsets resistant to anti-PD1 therapy, we investigated its role in inducing resistance. Phenotypic and functional characterization, along with single-cell RNA sequencing analysis of both in vitro chronically stimulated and intratumoral CD8+ T cells, revealed that CD38-expressing CD8+ T cells are terminally exhausted. Exploring the molecular mechanism, we found that CD38 expression was crucial in promoting terminal differentiation of CD8+ T cells by suppressing TCF1 expression, thereby rendering them unresponsive to anti-PD1 therapy. Genetic ablation of CD38 in tumor-reactive CD8+ T cells restored TCF1 levels and improved the responsiveness to anti-PD1 therapy in mice. Mechanistically, CD38 expression on exhausted CD8+ T cells elevated intracellular Ca2+ levels through RyR2 calcium channel activation. This, in turn, promoted chronic AKT activation, leading to TCF1 loss. Knockdown of RyR2 or inhibition of AKT in CD8+ T cells maintained TCF1 levels, induced a sustained anti-tumor response, and enhanced responsiveness to anti-PD1 therapy. Thus, targeting CD38 represents a potential strategy to improve the efficacy of anti-PD1 treatment in cancer.
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Linfócitos T CD8-Positivos , Neoplasias , Camundongos , Animais , Linfócitos T CD8-Positivos/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Subpopulações de Linfócitos T/metabolismoRESUMO
The characteristic expansion of T CD38high/HLA-DR+CD8+ lymphocytes observed in hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) proved able to distinguish HLH/MAS from sepsis and systemic juvenile idiopathic arthritis. However, the performance of this marker in differentiating HLH/MAS from other pediatric febrile conditions with similar clinical onset and yet entirely different treatments remains unexplored. CD38high/HLA-DR+CD8+ frequencies measured in the peripheral fresh blood of pediatric patients attended for suspicion of HLH/MAS were retrospectively recorded and clinical characteristics were retrieved. CD38high/HLA-DR+CD8+ frequencies in HLH/MAS patients (15 patients; median: 22.0%, IQR: 11.0-49.0%) were compared with those who presented febrile conditions other-than-HLH (28 patients; median: 13.0%, IQR: 3.9-28.7%; p = 0.24). HLH and non-HLH patients were subsequently regrouped based on the presence of an identified infection (22 patients; median: 27.0%, IQR: 15.2-72.1%) and compared with those without infections (21 patients; median: 7.6%, IQR: 3.7-24.3%; p = 0.0035). CD38high/HLA-DR+CD8+ percentages were significantly higher only in the infection group compared with the noninfection one, with a patent pathogen-specific expansion in Epstein-Barr virus primoinfection and visceral leishmaniasis regardless of the presence of HLH. CD38high/HLA-DR+CD8+ frequencies do not appear as an HLH-specific marker as they naturally expand in other clinical situations that are common in childhood and may mimic HLH initial presentation.
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Obstructive nephropathy is one of the leading causes of kidney injury and renal fibrosis in pediatric patients. Although considerable advances have been made in understanding the pathophysiology of obstructive nephropathy, most of them were based on animal experiments and a comprehensive understanding of obstructive nephropathy in pediatric patients at the molecular level remains limited. Here, we performed a comparative proteomics analysis of obstructed kidneys from pediatric patients with ureteropelvic junction obstruction and healthy kidney tissues. Intriguingly, the proteomics revealed extensive metabolic reprogramming in kidneys from individuals with ureteropelvic junction obstruction. Moreover, we uncovered the dysregulation of NAD+ metabolism and NAD+-related metabolic pathways, including mitochondrial dysfunction, the Krebs cycle, and tryptophan metabolism, which led to decreased NAD+ levels in obstructed kidneys. Importantly, the major NADase CD38 was strongly induced in human and experimental obstructive nephropathy. Genetic deletion or pharmacological inhibition of CD38 as well as NAD+ supplementation significantly recovered NAD+ levels in obstructed kidneys and reduced obstruction-induced renal fibrosis, partially through the mechanisms of blunting the recruitment of immune cells and NF-κB signaling. Thus, our work not only provides an enriched resource for future investigations of obstructive nephropathy but also establishes CD38-mediated NAD+ decline as a potential therapeutic target for obstruction-induced renal fibrosis.
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NAD , Obstrução Ureteral , Animais , Criança , Humanos , Fibrose , Rim/metabolismo , NAD/metabolismo , Proteômica , Obstrução Ureteral/complicações , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/metabolismoRESUMO
The numerous biological roles of NAD+ are organized and coordinated via its compartmentalization within cells. The spatial and temporal partitioning of this intermediary metabolite is intrinsic to understanding the impact of NAD+ on cellular signaling and metabolism. We review evidence supporting the compartmentalization of steady-state NAD+ levels in cells, as well as how the modulation of NAD+ synthesis dynamically regulates signaling by controlling subcellular NAD+ concentrations. We further discuss potential benefits to the cell of compartmentalizing NAD+, and methods for measuring subcellular NAD+ levels.
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Compartimento Celular , NAD/metabolismo , Frações Subcelulares/metabolismo , Animais , NAD/biossíntese , Transdução de SinaisRESUMO
Short telomeres are a principal defining feature of telomere biology disorders, such as dyskeratosis congenita (DC), for which there are no effective treatments. Here, we report that primary fibroblasts from DC patients and late generation telomerase knockout mice display lower nicotinamide adenine dinucleotide (NAD) levels, and an imbalance in the NAD metabolome that includes elevated CD38 NADase and reduced poly(ADP-ribose) polymerase and SIRT1 activities, respectively, affecting many associated biological pathways. Supplementation with the NAD precursor, nicotinamide riboside, and CD38 inhibition improved NAD homeostasis, thereby alleviating telomere damage, defective mitochondrial biosynthesis and clearance, cell growth retardation, and cellular senescence of DC fibroblasts. These findings reveal a direct, underlying role of NAD dysregulation when telomeres are short and underscore its relevance to the pathophysiology and interventions of human telomere-driven diseases.
Assuntos
Disceratose Congênita/genética , Disceratose Congênita/metabolismo , Fibroblastos/metabolismo , NAD/metabolismo , Telomerase/genética , Telômero/metabolismo , ADP-Ribosil Ciclase 1/genética , Animais , Encéfalo/patologia , Linhagem Celular , Senescência Celular , Disceratose Congênita/patologia , Feminino , Homeostase , Humanos , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Niacinamida/análogos & derivados , Niacinamida/metabolismo , Fenótipo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Compostos de Piridínio/metabolismo , Telomerase/metabolismoRESUMO
CD38 is a multifunctional enzyme implicated in chemotaxis of myeloid cells and lymphocyte activation, but also expressed by resident cells such as endothelial and smooth muscle cells. CD38 is important for host defense against microbes. However, CD38's role in the pathogenesis of atherosclerosis is controversial with seemingly conflicting results reported so far. To clarify the discrepancy of current literature on the effect of CD38 ablation on atherosclerosis development, we implanted a shear stress modifier around the right carotid artery in CD38-/- and WT mice. Hypercholesterolemia was induced by human gain-of-function PCSK9 (D374Y), introduced using AAV vector (serotype 9), combined with an atherogenic diet for a total of 9 weeks. Atherosclerosis was assessed at the aortic root, aortic arch and the right carotid artery. The findings can be summarized as follows: i) CD38-/- and WT mice had a similar atherosclerotic burden in all three locations, ii) No significant differences in monocyte infiltration or macrophage content could be seen in the plaques, and iii) The amount of collagen deposition in the plaques were also similar between CD38-/- and WT mice. In conclusion, our data suggest that CD38-/- mice are neither protected against nor prone to atherosclerosis compared to WT mice.
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Aterosclerose , Pró-Proteína Convertase 9 , Animais , Humanos , Camundongos , Aorta , Aterosclerose/genética , Aterosclerose/prevenção & controle , Artéria Carótida Primitiva , Antígenos CD/genética , Antígenos CD/metabolismoRESUMO
Acute and chronic viral infections result in the differentiation of effector and exhausted T cells with functional and phenotypic differences that dictate whether the infection is cleared or progresses to chronicity. High CD38 expression has been observed on CD8+ T cells across various viral infections and tumors in patients, suggesting an important regulatory function for CD38 on responding T cells. Here, we show that CD38 expression was increased and sustained on exhausted CD8+ T cells following chronic lymphocytic choriomeningitis virus (LCMV) infection, with lower levels observed on T cells from acute LCMV infection. We uncovered a cell-intrinsic role for CD38 expression in regulating the survival of effector and exhausted CD8+ T cells. We observed increased proliferation and function of Cd38-/- CD8+ progenitor exhausted T cells compared to those of wild-type (WT) cells. Furthermore, decreased oxidative phosphorylation and glycolytic potential were observed in Cd38-/- CD8+ T cells during chronic but not acute LCMV infection. Our studies reveal that CD38 has a dual cell-intrinsic function in CD8+ T cells, where it decreases proliferation and function yet supports their survival and metabolism. These findings show that CD38 is not only a marker of T cell activation but also has regulatory functions on effector and exhausted CD8+ T cells. IMPORTANCE Our study shows how CD38 expression is regulated on CD8+ T cells responding during acute and chronic viral infection. We observed higher CD38 levels on CD8+ T cells during chronic viral infection compared to levels during acute viral infection. Deleting CD38 had an important cell-intrinsic function in ensuring the survival of virus-specific CD8+ T cells throughout the course of viral infection. We found defective metabolism in Cd38-/- CD8+ T cells arising during chronic infection and changes in their progenitor T cell phenotype. Our studies revealed a dual cell-intrinsic role for CD38 in limiting proliferation and granzyme B production in virus-specific exhausted T cells while also promoting their survival. These data highlight new avenues for research into the mechanisms through which CD38 regulates the survival and metabolism of CD8+ T cell responses to viral infections.
Assuntos
Coriomeningite Linfocítica , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Diferenciação Celular/genética , Coriomeningite Linfocítica/metabolismo , Vírus da Coriomeningite Linfocítica/genética , Infecção Persistente , Animais , Camundongos , Sobrevivência Celular/genética , Regulação para Cima , Proliferação de Células/genéticaRESUMO
Psoriasis is a chronic, inflammatory skin disease characterized by a dysregulated immune response and systemic inflammation. Up to one-third of patients with psoriasis have psoriatic arthritis (PsA). Targeted treatment with antibodies neutralizing tumor necrosis factor (TNF) can ameliorate both diseases. We here explored the impact of long-term infliximab treatment on the composition and activity status of circulating immune cells involved in chronic skin and joint inflammation. Immune cells were analyzed by multicolor flow cytometry. We measured markers of immune activation in peripheral blood mononuclear cell (PBMC) populations in 24 infliximab-treated patients with psoriasis/psoriatic arthritis compared to 32 healthy controls. We observed a significant decrease in the frequency of both peripheral natural killer (NK) cells and their subset CD56dimCD16+ NK cells in PsA compared to healthy controls and patients with psoriasis. The latter had a strong positive correlation with PASI in these patients, while CD56brightCD16- NK cells were negatively correlated with PASI. In addition, we observed an upregulation of CD69+ intermediate CD14+CD16+ and CD69+ classical CD14+CD16- monocytes in PsA and increased activity of CD38+ intermediate CD14+CD16+ monocytes in patients with psoriasis. Compared to healthy controls, psoriasis patients demonstrated shifts of the three B cell subsets with a decrease in transitional CD27-CD38high B cells. Our exploratory study indicates a preserved pathophysiological process including continuous systemic inflammation despite clinical stability of the patients treated with infliximab.
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Cyclic ADP-ribose (cADPR) has emerged as a calcium-regulating second messenger in smooth muscle cells. CD38 protein possesses ADP-ribosyl cyclase and cADPR hydrolase activities and mediates cADPR synthesis and degradation. We have previously shown that CD38 expression is regulated by estrogen and progesterone in the myometrium. Considering hormonal regulation in gestation, the objective of the present study was to determine the role of CD38/cADPR signaling in the regulation of intracellular calcium upon contractile agonist stimulation using immortalized pregnant human myometrial (PHM1) cells. Western blot, immunofluorescence, and biochemical studies confirmed CD38 expression and the presence of ADP-ribosyl cyclase (2.6 ± 0.1 pmol/mg) and cADPR hydrolase (26.8 ± 6.8 nmoles/mg/h) activities on the PHM1 cell membrane. Oxytocin, PGF2α, and ET-1 elicited [Ca2+]i responses, and 8-Br-cADPR, a cADPR antagonist significantly attenuated agonist-induced [Ca2+]i responses between 20% and 46% in average. The findings suggest that uterine contractile agonists mediate their effects in part through CD38/cADPR signaling to increase [Ca2+]i and presumably uterine contraction. As studies in humans are limited by the availability of myometrium from healthy donors, PHM1 cells form an in vitro model to study human myometrium.
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To retrospectively analyze whether the second revision of the international staging system (R2-ISS) influenced prognosis at treatment initiation in patients with multiple myeloma (MM) receiving anti-CD38 antibody-based triplet treatments. High-risk chromosomal abnormalities were examined from diagnosis to treatment initiation and considered positive if detected once. R2-ISS was recalculated at the initiation of treatment and defined as "dynamic R2-ISS." Data from 150 patients who underwent the defined treatments were analyzed. The median progression-free survival (PFS) was 19.5 months, and the median overall survival (OS) was 36.5 months. Dynamic R2-ISS significantly stratified prognoses for both PFS and OS. The median PFS for patients with dynamic R2-ISS IV was 3.3 months, and the median OS was 11.7 months, indicating extremely poor outcomes. Although the Revised International Staging System (R-ISS) calculated at the initiation of treatment significantly stratified treatment outcomes, the patients classified as R-ISS could be further stratified by R2-ISS to provide better prognostic information. Dynamic R2-ISS showed potential as a prognostic tool in patients with MM who are treated with anti-CD38 antibody-based triplet therapies.
Assuntos
ADP-Ribosil Ciclase 1 , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Mieloma Múltiplo/patologia , Masculino , Feminino , ADP-Ribosil Ciclase 1/antagonistas & inibidores , Pessoa de Meia-Idade , Idoso , Prognóstico , Estudos Retrospectivos , Adulto , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estadiamento de Neoplasias , Taxa de Sobrevida , Glicoproteínas de MembranaRESUMO
CD38 is involved in immune responses, cell proliferation, and has been identified in the brain, where it is implicated in inflammation processes and psychiatric disorders. We hypothesized that dysfunctional CD38 activity in the brain may contribute to the pathogenesis of depression. To investigate the underlying mechanisms, we used a lipopolysaccharide (LPS)-induced depression-like model and conducted behavioral tests, molecular and morphological methods, along with optogenetic techniques. We microinjected adeno-associated virus into the hippocampal CA3 region with stereotaxic instrumentation. Our results showed a marked increase in CD38 expression in both the hippocampus and cortex of LPS-treated mice. Additionally, pharmacological inhibition and genetic knockout of CD38 effectively alleviated neuroinflammation, microglia activation, synaptic defects, and Sirt1/STAT3 signaling, subsequently improving depression-like behaviors. Moreover, optogenetic activation of glutamatergic neurons of hippocampal CA3 reduced the susceptibility of mice to depression-like behaviors, accompanied by reduced CD38 expression. We also found that (R)-ketamine, which displayed antidepressant effects, was linked to its anti-inflammatory properties by suppressing increased CD38 expression and reversing synaptic defects. In conclusion, hippocampal CD38 is closely linked to depression-like behaviors in an inflammation model, highlighting its potential as a therapeutic target for antidepressant development.
Assuntos
ADP-Ribosil Ciclase 1 , Depressão , Ketamina , Animais , Camundongos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Antidepressivos/metabolismo , Depressão/metabolismo , Hipocampo/metabolismo , Inflamação/metabolismo , Ketamina/farmacologia , Ketamina/uso terapêutico , Ketamina/metabolismo , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/metabolismo , ADP-Ribosil Ciclase 1/metabolismoRESUMO
BACKGROUND: Drugs such as daratumumab (Darzalex, anti-CD38) and Hu5F9-G4 (magrolimab, anti-CD47) may interfere with red blood cell compatibility testing as CD38 and CD47 are expressed on red blood cells. STUDY DESIGN AND METHODS: A survey of AABB member transfusion services was undertaken to understand their experiences of managing patients taking therapeutic monoclonal antibodies that are known to interfere with blood grouping and compatibility testing. RESULTS: The survey was distributed to the contact person at US-based AABB member transfusion services. The response rate was 27%. 172 of 240 (72%) indicated they had difficulties in performing compatibility testing in patients taking daratumumab and 66 of 91 (73%) reported difficulties in performing compatibility testing in patients taking magrolimab. Actions taken to provide compatible blood for these patients included referral of all samples to a reference center, blood group pheno/genotyping the patient in advance of starting the drug, treating reagent cells with 0.2 M dithiothreitol and using K-negative red cell units for patients taking daratumumab, and Gamma-clone (Immucor) anti-IgG for indirect antiglobulin testing for patients taking magrolimab. Lack of communication from clinical services about drug treatment was identified as a concern. CONCLUSION: The results of the survey demonstrate that transfusion services are having challenges with the transfusion management of patients taking therapeutic monoclonal antibodies, and further education is needed.
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ADP-Ribosil Ciclase 1 , Anticorpos Monoclonais Humanizados , Anticorpos Monoclonais , Antígeno CD47 , Humanos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Tipagem e Reações Cruzadas Sanguíneas , Eritrócitos/imunologia , Incompatibilidade de Grupos Sanguíneos , Transfusão de Sangue , Inquéritos e Questionários , Glicoproteínas de MembranaRESUMO
Relapsed/refractory acute leukemia (R/R-AL) is associated with a low remission rate, short survival rate, and poor prognosis. Treating R/R-AL remains challenging as there is no standardized effective regimen; hence, there is a need for efficient therapies. CD38 expression has been observed in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Daratumumab is a humanized anti-CD38 monoclonal antibody used to treat multiple myeloma and has been reported to treat R/R-AL safely and effectively. The clinical data of 10 adult patients with R/R-AL who were treated with a daratumumab-based salvage regimen between July 2018 and May 2023 at our center were analyzed retrospectively. Seven AML and three ALL cases were included in the analysis. Seven (70%) patients showed responses to the treatments (complete response [CR], 60%; partial response [PR], 10%). Of the seven responders, three underwent allogenic stem cell transplantation (ASCT), including one who underwent a second ASCT. Among the five patients with R/R AML who had prior exposure to venetoclax, three achieved a therapeutic response (two CR and one PR) when re-treated with venetoclax in combination with daratumumab. The median follow-up time was 6.15 months (0.9-21 months). Overall survival and event-free survival rates at 12 months were 68.6% and 40.0%, respectively. The main adverse events included grade 3 febrile neutropenia (20%) and grade 3 hematological toxicities (60%). The daratumumab-based salvage regimen offers patients with R/R-AL the opportunity of remission with acceptable tolerability, creating the possibility of bridging ASCT.
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Idebenone, an antioxidant used in treating oxidative damage-related diseases, has unclear neuroprotective mechanisms. Oxidative stress affects cell and mitochondrial membranes, altering Adp-ribosyl cyclase (CD38) and Silent message regulator 3 (SIRT3) protein expression and possibly impacting SIRT3's ability to deacetylate Tumor protein p53 (P53). This study explores the relationship between CD38, SIRT3, and P53 in H2O2-injured HT22 cells treated with Idebenone. Apoptosis was detected using flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining after determining appropriate H2O2 and Idebenone concentrations.In this study, Idebenone was found to reduce apoptosis and decrease P53 and Caspase3 expression in H2O2-injured HT22 cells by detecting apoptosis-related protein expression. Through bioinformatics methods, CD38 was identified as the target of Idebenone, and it further demonstrated that Idebenone decreased the expression of CD38 and increased the level of SIRT3. An increased NAD+/NADH ratio was detected, suggesting Idebenone induces SIRT3 expression and protects HT22 cells by decreasing apoptosis-related proteins. Knocking down SIRT3 downregulated acetylated P53 (P53Ac), indicating SIRT3's importance in P53 deacetylation.These results supported that CD38 was used as a target of Idebenone to up-regulate SIRT3 to deacetylate activated P53, thereby protecting HT22 cells from oxidative stress injury. Thus, Idebenone is a drug that may show great potential in protecting against reactive oxygen species (ROS) induced diseases such as Parkinson's disease, and Alzheimer's disease. And it might be able to compensate for some of the defects associated with CD38-related diseases.
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ADP-Ribosil Ciclase 1 , Apoptose , Estresse Oxidativo , Sirtuína 3 , Proteína Supressora de Tumor p53 , Ubiquinona , Proteína Supressora de Tumor p53/metabolismo , Estresse Oxidativo/efeitos dos fármacos , ADP-Ribosil Ciclase 1/metabolismo , Animais , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Camundongos , Sirtuína 3/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Peróxido de Hidrogênio/toxicidade , Antioxidantes/farmacologia , Glicoproteínas de Membrana/metabolismo , Fármacos Neuroprotetores/farmacologiaRESUMO
Assessing CD38 expression in vivo has become a significant element in multiple myeloma (MM) therapy, as it can be used to detect lesions and forecast the effectiveness of treatment. Accurate diagnosis requires a multifunctional, high-throughput probe screening platform to develop molecular probes for tumor-targeted multimodal imaging and treatment. Here, we investigated a microarray chip-based strategy for high-throughput screening of peptide probes for CD38. We obtained two new target peptides, CA-1 and CA-2, from a 105 peptide library with a dissociation constant (KD) of 10-7 M. The specificity and affinity of the target peptides were confirmed at the molecular and cellular levels. Peptide probes were labeled with indocyanine green (ICG) dye and 68Ga-DOTA, which were injected into a CD38-positive Ramos tumor-bearing mouse via its tail vein, and small animal fluorescence and positron emission tomography (PET) imaging showed that the peptide probes could show specific enrichment in the tumor tissue. Our study shows that a microchip-based screening of peptide probes can be used as a promising imaging tool for MM diagnosis.
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Mieloma Múltiplo , Camundongos , Animais , Mieloma Múltiplo/diagnóstico por imagem , Linhagem Celular Tumoral , Tomografia por Emissão de Pósitrons/métodos , Peptídeos/química , Imagem Multimodal/métodos , Radioisótopos de Gálio/químicaRESUMO
OBJECTIVES: Cluster of differentiation 38 (CD38) is a key target on multiple myeloma (MM) cells. This multi-centre, Phase 1, single-agent study (NCT04000282) investigated SAR442085, a novel fragment crystallisable (Fc)-modified anti-CD38 monoclonal antibody (mAb), with enhanced affinity towards Fc-gamma receptor on effector cells in patients with relapsed and/or refractory (RR) MM. METHODS: This study comprised two parts: Part-A (dose-escalation involving anti-CD38 mAb pre-treated and naïve patients) and Part-B (dose expansion). Primary endpoints were maximum tolerated dose and recommended Phase 2 dose (RP2D). RESULTS: Thirty-seven heavily pre-treated patients were treated in Part A. Part-B (dose-expansion) was not studied. Seven dose-limiting toxicities were reported at DL3, DL5, DL6, and DL7. RP2D was determined to be 5-7·5 mg/kg. Most common treatment-emergent adverse events were infusion-related reactions in 70·3% (26/37) patients. Grade ≥3 thrombocytopenia was reported in 48·6% (18/37). Overall response rate was 70% in anti-CD38 mAb naïve and 4% in anti-CD38 pre-treated patients, with a median progression-free survival of 7·62 (95%CI: 2·858; not calculable) months and 2·79 (95%CI: 1·150; 4·172) months and, respectively. CONCLUSIONS: The efficacy of SAR442085 was promising in anti-CD38 mAb naïve patients but did not extend to the larger cohort of anti-CD38 mAb pre-treated patients. This observation, along with transient high-grade thrombocytopenia, could potentially limit its clinical use.
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OBJECTIVES: Cellular NAD+ declines in inflammatory states associated with increased activity of the leukocyte-expressed NADase CD38. In this study, we tested the potential role of therapeutically targeting CD38 and NAD+ in gout. METHODS: We studied cultured mouse wild type and CD38 knockout (KO) murine bone marrow derived macrophages (BMDMs) stimulated by monosodium urate (MSU) crystals and used the air pouch gouty inflammation model. RESULTS: MSU crystals induced CD38 in BMDMs in vitro, associated with NAD+ depletion, and IL-1ß and CXCL1 release, effects reversed by pharmacologic CD38 inhibitors (apigenin, 78c). Mouse air pouch inflammatory responses to MSU crystals were blunted by CD38 KO and apigenin. Pharmacologic CD38 inhibition suppressed MSU crystal-induced NLRP3 inflammasome activation and increased anti-inflammatory SIRT3-SOD2 activity in macrophages. BMDM RNA-seq analysis of differentially expressed genes (DEGs) revealed CD38 to control multiple MSU crystal-modulated inflammation pathways. Top DEGs included the circadian rhythm modulator GRP176, and the metalloreductase STEAP4 that mediates iron homeostasis, and promotes oxidative stress and NF-κB activation when it is overexpressed. CONCLUSIONS: CD38 and NAD+ depletion are druggable targets controlling the MSU crystal- induced inflammation program. Targeting CD38 and NAD+ are potentially novel selective molecular approaches to limit gouty arthritis.
Assuntos
ADP-Ribosil Ciclase 1 , Inflamação , Macrófagos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NAD , Ácido Úrico , Animais , ADP-Ribosil Ciclase 1/genética , ADP-Ribosil Ciclase 1/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Inflamação/tratamento farmacológico , Camundongos , NAD/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Células Cultivadas , Artrite Gotosa/tratamento farmacológico , Artrite Gotosa/metabolismo , Artrite Gotosa/genética , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacosRESUMO
BACKGROUND: Rickets occurs in infants and children (aged 2 months to 3 years), compromising their skeletal development and damaging nervous, hematopoietic, immune, and other system functions. This study aimed to explore the significance of CD38 in rickets. METHODS: The microarray dataset GSE22523 was analyzed to obtain differentially expressed genes in rickets patients. A total of 36 rickets patients and healthy controls were recruited for the study, and their blood samples were collected, followed by detecting mRNA levels of CD38 using quantitative real-time polymerase chain reaction (qRT-PCR). Moreover, the significance of CD38 in rickets patients was analyzed by receiver operating characteristic (ROC) analysis, while the correlation between CD38 and 25-hydroxy-vitamin D (25OHD)/parathyroid hormone (PTH) was analyzed with Pearson's correlation. RESULTS: Results showed that CD38 mRNA levels and PTH contents were significantly increased in the rickets patients while 25OHD contents were decreased. Correlation analysis indicated that CD38 was positively correlated with PTH and negatively correlated with 25OHD in both serum and plasma samples of rickets patients. Moreover, ROC analysis showed that serum CD38 was 0.9005 (95 % CI: 0.8313-0.9696), and the AUCs of plasma CD38 was 0.7215 (95 % CI: 0.6031-0.8398) in differentiating rickets patients from healthy persons, advocating serum CD38 had better diagnostic value. CONCLUSION: CD38 mRNA levels were upregulated in rickets patients and closely correlated with PTH and 25OHD contents, indicating CD38 might be a diagnostic marker of rickets patients. Further research on the diagnostic utility of CD38 is necessary for the diagnosis and treatment of ricketsin rickets in the future.