RESUMEN

Myocardial ischemia-reperfusion (I/R) injury exacerbates cellular damage upon restoring blood flow to ischemic cardiac tissue, causing oxidative stress, inflammation, and apoptosis. This study investigates Nicotinamide Riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD+), for its cardioprotective effects. Administering NR to mice before I/R injury and evaluating heart function via echocardiography showed that NR significantly improved heart function, increased left ventricular ejection fraction (LVEF) and fractional shortening (FS), and reduced left ventricular end-diastolic (LVDd) and end-systolic diameters (LVSd). NR also restored E/A and E/e' ratios. It reduced cardiomyocyte apoptosis both in vivo and in vitro, inhibiting elevated caspase-3 activity and returning Bax protein levels to normal. In vitro, NR reduced the apoptotic rate in hydrogen peroxide (H2O2)-treated HL-1 cells from 30% to 10%. Mechanistically, NR modulated the SIRT3/mtROS/JNK pathway, reversing H2O2-induced SIRT3 downregulation, reducing mitochondrial reactive oxygen species (mtROS), and inhibiting JNK activation. Using SIRT3-knockout (SIRT3-KO) mice, we confirmed that NR's cardioprotective effects depend on SIRT3. Echocardiography showed that NR's benefits were abrogated in SIRT3-KO mice. In conclusion, NR provides significant cardioprotection against myocardial I/R injury by enhancing NAD+ levels and modulating the SIRT3/mtROS/JNK pathway, suggesting its potential as a novel therapeutic agent for ischemic heart diseases, meriting further clinical research.

Asunto(s)

Apoptosis , Ratones Noqueados , Daño por Reperfusión Miocárdica , Niacinamida , Compuestos de Piridinio , Especies Reactivas de Oxígeno , Sirtuina 3 , Animales , Sirtuina 3/metabolismo , Sirtuina 3/genética , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Niacinamida/análogos & derivados , Niacinamida/farmacología , Niacinamida/uso terapéutico , Ratones , Compuestos de Piridinio/farmacología , Compuestos de Piridinio/administración & dosificación , Especies Reactivas de Oxígeno/metabolismo , Apoptosis/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Estrés Oxidativo/efectos de los fármacos , Humanos , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Modelos Animales de Enfermedad , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacos

RESUMEN

Dollar spot, a highly destructive turfgrasses disease worldwide, is caused by multiple species within the genus Clarireedia. Previous research indicated varying sensitivity to boscalid among Clarireedia populations not historically exposed to succinate dehydrogenase inhibitors (SDHIs). This study confirms that the differential sensitivity pattern is inherent among different Clarireedia spp., utilizing a combination of phylogenetic analyses, in vitro cross-resistance assays, and genetic transformation of target genes with different mutations. Furthermore, greenhouse inoculation experiments revealed that the differential boscalid sensitivity did not lead to pathogenicity issues or fitness penalties, thereby not resulting in control failure by boscalid. This research underscores the importance of continuous monitoring of fungicide sensitivity trends and highlights the complexity of chemical control of dollar spot due to the inherent variability in fungicide sensitivity among different Clarireedia spp.

Asunto(s)

Compuestos de Bifenilo , Fungicidas Industriales , Niacinamida , Enfermedades de las Plantas , Fungicidas Industriales/farmacología , Compuestos de Bifenilo/farmacología , Enfermedades de las Plantas/microbiología , Niacinamida/análogos & derivados , Niacinamida/farmacología , Poaceae/microbiología , Filogenia , Farmacorresistencia Fúngica/genética , Succinato Deshidrogenasa/genética , Succinato Deshidrogenasa/antagonistas & inhibidores , Basidiomycota/genética , Basidiomycota/efectos de los fármacos

RESUMEN

The destructive disease gray leaf spot, caused by Stemphylium solani, is prevalent in tomato plants in China. A variety of fungicides have been extensively used for controlling the disease, with a particular focus on succinate dehydrogenase inhibitors (SDHIs) and quinone outside inhibitors (QoIs). However, there was a lack of information regarding the resistance of S. solani to boscalid (SDHI) and pyraclostrobin (QoI) in China. In this study, the sensitivity of S. solani to boscalid and pyraclostrobin was monitored. The EC50 values for boscalid ranged from 0.02 to 3.0 µg∙mL-1, with an average value of 0.62 µg∙mL-1, while the EC50 values for pyraclostrobin ranged from 0.21 to 14.71 µg∙mL-1, with an average value of 6.03 µg∙mL-1. Based on these findings, the frequencies of observed resistance were as follows: 36.7% for boscalid and 50% for pyraclostrobin; while the resistance frequency to both boscalid and pyraclostrobin in S. solani was 19.4%. The mutation associated with boscalid resistance in S. solani within tomato fields was identified as SdhB-H277Y, while the mutation related to pyraclostrobin resistance was found in cytochrome b, specifically Cytb-G143A. The resistant mutants displayed diminished fitness in terms of mycelial growth, yet their pathogenicity exhibited no significant disparities. To delay the development of resistance, it is advisable to employ a rotation strategy using alternative fungicides with different modes of action or mix with fungicides with multi-site-contact activity for disease management.

Asunto(s)

Ascomicetos , Compuestos de Bifenilo , Farmacorresistencia Fúngica , Fungicidas Industriales , Niacinamida , Enfermedades de las Plantas , Solanum lycopersicum , Estrobilurinas , Estrobilurinas/farmacología , Solanum lycopersicum/microbiología , Fungicidas Industriales/farmacología , Enfermedades de las Plantas/microbiología , Niacinamida/farmacología , Niacinamida/análogos & derivados , Farmacorresistencia Fúngica/genética , China , Compuestos de Bifenilo/farmacología , Ascomicetos/efectos de los fármacos , Ascomicetos/patogenicidad

RESUMEN

Glaucoma is a blinding disease where the retinal ganglion cells and their axons degenerate. Degradation of axonal microtubules is thought to play a critical role in the pathogenesis, but the mechanism is unknown. Here we investigate whether microtubule disruption in glaucoma can be alleviated by metabolic rescue. The integrity of axonal microtubules and the morphology of the retinal nerve fibers were evaluated by second-harmonic generation microscopy in a mouse model of glaucoma, DBA/2J, which received a dietary supplement of nicotinamide (NAM) for reducing metabolic stress. It was compared with control DBA/2J, which did not receive NAM, and non-glaucomatous DBA/2J-Gpnmb+. We found that the morphology of the retinal nerve fibers, but not axonal microtubules, are significantly protected by NAM. The decoupling is analogous to microtubule deficit, a glaucoma pathology in which axonal microtubules exhibit rapid degradation compared to the morphology of the retinal nerve fibers. Understanding microtubule deficit could provide insights into the divergent responses to NAM. From co-registered images of second-harmonic generation and immunofluorescence, it was determined that microtubule deficit was not due to a shortage of tubulins. Furthermore, microtubule deficit colocalized with the sectors in which the retinal ganglion cells were disconnected from the brain, suggesting that microtubule disruption is associated with axonal transport deficit in glaucoma. Together, our data suggests significant role axonal microtubules play in glaucomatous degeneration, offering a new opportunity for neuroprotection.

Asunto(s)

Modelos Animales de Enfermedad , Glaucoma , Ratones Endogámicos DBA , Microtúbulos , Niacinamida , Células Ganglionares de la Retina , Animales , Glaucoma/patología , Glaucoma/metabolismo , Glaucoma/tratamiento farmacológico , Niacinamida/farmacología , Niacinamida/uso terapéutico , Ratones , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/patología , Células Ganglionares de la Retina/metabolismo , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Axones/efectos de los fármacos , Axones/metabolismo , Axones/patología , Microscopía/métodos , Fibras Nerviosas/efectos de los fármacos , Fibras Nerviosas/patología , Fibras Nerviosas/metabolismo

RESUMEN

Cellular NAD+ is continuously degraded and synthesized under resting conditions. In mammals, NAD+ synthesis is primarily initiated from nicotinamide (Nam) by Nam phosphoribosyltransferase, whereas poly(ADP-ribose) polymerase 1 (PARP1) and 2 (PARP2), sirtuin1 (SIRT1), CD38, and sterile alpha and TIR motif containing 1 (SARM1) are involved in NAD+ breakdown. Using flux analysis with 2H-labeled Nam, we found that when mammalian cells were cultured in the absence of Nam, cellular NAD+ levels were maintained and NAD+ breakdown was completely suppressed. In the presence of Nam, the rate of NAD+ breakdown (RB) did not significantly change upon PARP1, PARP2, SIRT1, or SARM1 deletion, whereas stable expression of CD38 did not increase RB. However, RB in PARP1-deleted cells was much higher compared with that in wild-type cells, in which PARP1 activity was blocked with a selective inhibitor. In contrast, RB in CD38-overexpressing cells in the presence of a specific CD38 inhibitor was much lower compared with that in control cells. The results indicate that PARP1 deletion upregulates the activity of other NADases, whereas CD38 expression downregulates the activity of endogenous NADases, including PARP1 and PARP2. The rate of cellular NAD+ breakdown and the resulting NAD+ concentration may be maintained at a constant level, despite changes in the NAD+-degrading enzyme expression, through the compensatory regulation of NADase activity.

Asunto(s)

ADP-Ribosil Ciclasa 1 , NAD , Poli(ADP-Ribosa) Polimerasa-1 , Sirtuina 1 , NAD/metabolismo , ADP-Ribosil Ciclasa 1/metabolismo , ADP-Ribosil Ciclasa 1/genética , Animales , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Sirtuina 1/metabolismo , Sirtuina 1/genética , Niacinamida/farmacología , Niacinamida/metabolismo , Ratones , Poli(ADP-Ribosa) Polimerasas/metabolismo , Humanos , Nicotinamida Fosforribosiltransferasa/metabolismo , Nicotinamida Fosforribosiltransferasa/genética , Eliminación de Gen

RESUMEN

Dendritic cells (DCs) are crucial in initiating and shaping both innate and adaptive immune responses. Clinical studies and experimental models have highlighted their significant involvement in various autoimmune diseases, positioning them as promising therapeutic targets. Nicotinamide (NAM), a form of vitamin B3, with its anti-inflammatory properties, has been suggested, while the involvement of NAM in DCs regulation remains elusive. Here, through analyzing publicly available databases, we observe substantial alterations in NAM levels and NAM metabolic pathways during DCs activation. Furthermore, we discover that NAM, but not Nicotinamide Mononucleotide (NMN), significantly inhibits DCs over-activation in vitro and in vivo. The suppression of DCs hyperactivation effectively alleviates symptoms of psoriasis. Mechanistically, NAM impairs DCs activation through a Poly (ADP-ribose) polymerases (PARPs)-NF-κB dependent manner. Notably, phosphoribosyl transferase (NAMPT) and PARPs are significantly upregulated in lipopolysaccharide (LPS)-stimulated DCs and psoriasis patients; elevated NAMPT and PARPs expression in psoriasis patients correlates with higher psoriasis area and severity index (PASI) scores. In summary, our findings underscore the pivotal role of NAM in modulating DCs functions and autoimmune disorders. Targeting the NAMPT-PARP axis emerges as a promising therapeutic approach for DC-related diseases.

Asunto(s)

Enfermedades Autoinmunes , Células Dendríticas , Niacinamida , Nicotinamida Fosforribosiltransferasa , Poli(ADP-Ribosa) Polimerasas , Psoriasis , Transducción de Señal , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Células Dendríticas/inmunología , Niacinamida/farmacología , Humanos , Transducción de Señal/efectos de los fármacos , Animales , Psoriasis/tratamiento farmacológico , Psoriasis/inmunología , Psoriasis/metabolismo , Enfermedades Autoinmunes/tratamiento farmacológico , Nicotinamida Fosforribosiltransferasa/metabolismo , Ratones , Poli(ADP-Ribosa) Polimerasas/metabolismo , FN-kappa B/metabolismo , Ratones Endogámicos C57BL , Lipopolisacáridos

RESUMEN

Freesia refracta (FR), a perennial flower of the Iris family (Iridaceae), is widely used in cosmetics despite limited scientific evidence of its skin benefits and chemical composition, particularly of FR callus extract (FCE). This study identified biologically active compounds in FCE and assessed their skin benefits, focusing on anti-aging. FR calli were cultured, extracted with water at 40 °C, and analyzed using Centrifugal Partition Chromatography (CPC), Nuclear Magnetic Resonance (NMR), and HCA, revealing key compounds, namely nicotinamide and pyroglutamic acid. FCE significantly increased collagen I production by 52% in normal and aged fibroblasts and enhanced fibroblast-collagen interaction by 37%. An in vivo study of 43 female volunteers demonstrated an 11.1% reduction in skin roughness and a 2.3-fold increase in collagen density after 28 days of cream application containing 3% FCE. Additionally, the preservation tests of cosmetics containing FCE confirmed their stability over 12 weeks. These results suggest that FCE offers substantial anti-aging benefits by enhancing collagen production and fibroblast-collagen interactions. These findings highlighted the potential of FCE in cosmetic applications, providing significant improvements in skin smoothness and overall appearance. This study fills a gap in the scientific literature regarding the skin benefits and chemical composition of FR callus extract, supporting its use in the development of effective cosmeceuticals.

Asunto(s)

Fibroblastos , Estrés Oxidativo , Extractos Vegetales , Envejecimiento de la Piel , Piel , Envejecimiento de la Piel/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/química , Humanos , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Piel/metabolismo , Piel/efectos de los fármacos , Transcriptoma/efectos de los fármacos , Adulto , Colágeno/metabolismo , Cosméticos/farmacología , Persona de Mediana Edad , Niacinamida/farmacología , Ácido Pirrolidona Carboxílico/análogos & derivados , Ácido Pirrolidona Carboxílico/farmacología , Ácido Pirrolidona Carboxílico/metabolismo

RESUMEN

This study is focused on the utilization of naturally occurring salicylic acid and nicotinamide (vitamin B3) in the development of novel sustainable Active Pharmaceutical Ingredients (APIs) with significant potential for treating acne vulgaris. The study highlights how the chemical structure of the cation significantly influences surface activity, lipophilicity, and solubility in aqueous media. Furthermore, the new ionic forms of APIs, the synthesis of which was assessed with Green Chemistry metrics, exhibited very good antibacterial properties against common pathogens that contribute to the development of acne, resulting in remarkable enhancement of biological activity ranging from 200 to as much as 2000 times when compared to salicylic acid alone. The molecular docking studies also revealed the excellent anti-inflammatory activity of N-alkylnicotinamide salicylates comparable to commonly used drugs (indomethacin, ibuprofen, and acetylsalicylic acid) and were even characterized by better IC50 values than common anti-inflammatory drugs in some cases. The derivative, featuring a decyl substituent in the pyridinium ring of nicotinamide, exhibited efficacy against Cutibacterium acnes while displaying favorable water solubility and improved wettability on hydrophobic surfaces, marking it as particularly promising. To investigate the impact of the APIs on the biosphere, the EC50 parameter was determined against a model representative of crustaceans─Artemia franciscana. The majority of compounds (with the exception of the salt containing the dodecyl substituent) could be classified as "Relatively Harmless" or "Practically Nontoxic", indicating their potential low environmental impact, which is essential in the context of modern drug development.

Asunto(s)

Acné Vulgar , Antibacterianos , Simulación del Acoplamiento Molecular , Niacinamida , Acné Vulgar/tratamiento farmacológico , Niacinamida/química , Niacinamida/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Humanos , Solubilidad , Salicilatos/química , Salicilatos/farmacología , Pruebas de Sensibilidad Microbiana , Sales (Química)/química , Propionibacteriaceae/efectos de los fármacos , Antiinflamatorios/química , Antiinflamatorios/farmacología , Aniones/química , Ácido Salicílico/química , Ácido Salicílico/farmacología

RESUMEN

Friedreich's ataxia (FRDA) is a progressive disorder caused by insufficient expression of frataxin, which plays a critical role in assembly of iron-sulfur centers in mitochondria. Individuals are cognitively normal but display a loss of motor coordination and cardiac abnormalities. Many ultimately develop heart failure. Administration of nicotinamide adenine dinucleotide-positive (NAD+) precursors has shown promise in human mitochondrial myopathy and rodent models of heart failure, including mice lacking frataxin in cardiomyocytes. We studied mice with systemic knockdown of frataxin (shFxn), which display motor deficits and early mortality with cardiac hypertrophy. Hearts in these mice do not "fail" per se but become hyperdynamic with small chamber sizes. Data from an ongoing natural history study indicate that hyperdynamic hearts are observed in young individuals with FRDA, suggesting that the mouse model could reflect early pathology. Administering nicotinamide mononucleotide or riboside to shFxn mice increases survival, modestly improves cardiac hypertrophy, and limits increases in ejection fraction. Mechanistically, most of the transcriptional and metabolic changes induced by frataxin knockdown are insensitive to NAD+ precursor administration, but glutathione levels are increased, suggesting improved antioxidant capacity. Overall, our findings indicate that NAD+ precursors are modestly cardioprotective in this model of FRDA and warrant further investigation.

Asunto(s)

Modelos Animales de Enfermedad , Frataxina , Ataxia de Friedreich , Proteínas de Unión a Hierro , NAD , Animales , Ataxia de Friedreich/metabolismo , Ataxia de Friedreich/patología , Ataxia de Friedreich/genética , Proteínas de Unión a Hierro/genética , Proteínas de Unión a Hierro/metabolismo , Ratones , Humanos , NAD/metabolismo , Fenotipo , Masculino , Cardiomegalia/metabolismo , Cardiomegalia/patología , Mononucleótido de Nicotinamida/farmacología , Niacinamida/análogos & derivados , Niacinamida/farmacología , Femenino , Técnicas de Silenciamiento del Gen , Compuestos de Piridinio , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología

RESUMEN

OBJECTIVES: Flotillin-2 (FLOT2) is a prototypical oncogenic and a potential target for cancer therapy. However, strategies for targeting FLOT2 remain undefined. Post-translational modifications are crucial for regulating protein stability, function, and localization. Understanding the mechanisms and roles of post-translational modifications is key to developing targeted therapies. This study aims to investigate the regulation and function of lysine acetylation of FLOT2 in nasopharyngeal carcinoma, providing new insights for targeting FLOT2 in cancer intervention. METHODS: The PhosphoSitePlus database was used to analyze the lysine acetylation sites of FLOT2, and a lysine acetylation site mutation of FLOT2 [FLOT2 (K211R)] was constructed. Nasopharyngeal carcinoma cells were treated with histone deacetylase (HDAC) inhibitor trichostatin A (TSA) and Sirt family deacetylase inhibitor nicotinamide (NAM). TSA-treated human embryonic kidney (HEK)-293T were transfected with FLOT2 mutant plasmids. Co-immunoprecipitation (Co-IP) was used to detect total acetylation levels of FLOT2 and the effects of specific lysine (K) site mutations on FLOT2 acetylation. Western blotting was used to detect FLOT2/FLAG-FLOT2 protein expression in TSA-treated nasopharyngeal carcinoma cells transfected with FLOT mutant plasmids, and real-time reverse transcription PCR (real-time RT-PCR) was used to detect FLOT2 mRNA expression. Nasopharyngeal carcinoma cells were treated with TSA combined with MG132 or chloroquine (CQ) to analyze FLOT2 protein expression. Cycloheximide (CHX) was used to treat HEK-293T cells transfected with FLAG-FLOT2 (WT) or FLAG-FLOT2(K211R) plasmids to assess protein degradation rates. The BioGrid database was used to identify potential interactions between FLOT2 and HDAC6, which were validated by Co-IP. HEK-293T cells were co-transfected with FLAG-FLOT2 (WT)/FLAG-FLOT2 (K211R) and Vector/HDAC6 plasmids, and grouped into FLAG-FLOT2 (WT)+Vector, FLAG-FLOT2 (WT)+HDAC6, FLAG-FLOT2 (K211R)+Vector, and FLAG-FLOT2 (K211R)+HDAC6 to analyze the impact of K211R mutation on total lysine acetylation levels. In 6-0B cells, overexpression of FLOT2 (WT) and FLOT2 (K211R) was performed, and the biological functions of FLOT2 acetylation site mutants were assessed using cell counting kit-8 (CCK-8), colony formation, and Transwell invasion assays. RESULTS: The PhosphoSitePlus database indicated that FLOT2 has an acetylation modification at the K211 site. Co-IP confirmed significant acetylation of FLOT2, with TSA significantly increasing overall FLOT2 acetylation levels, while NAM had no effect. Mutation at the K211 site significantly reduced overall FLOT2 acetylation, unaffected by TSA. TSA decreased FLOT2 protein expression in nasopharyngeal carcinoma cells without affecting FLOT2 mRNA levels or FLOT2 (K211R) protein expression in transfected cells. The degradation rate of FLOT2 (K211R) protein was significantly slower than that of FLOT2 (WT). The proteasome inhibitor MG132 prevented TSA-induced FLOT2 degradation, while the lysosome inhibitor CQ did not. BioGrid data suggested a potential interaction between FLOT2 and HDAC6, confirmed by Co-IP. Knockdown of HDAC6 in nasopharyngeal carcinoma cells significantly increased FLOT2 acetylation; co-transfection of HDAC6 and FLAG-FLOT2 (WT) significantly decreased total lysine acetylation levels, whereas co-transfection of HDAC6 and FLAG-FLOT2 (K211R) had no effect. Knockdown of HDAC6 significantly reduced FLOT2 protein levels without affecting mRNA levels. MG132 prevented HDAC6-knockdown-induced FLOT2 degradation. Knockdown of HDAC6 significantly accelerated FLOT2 degradation. Nasopharyngeal carcinoma cells transfected with FLOT2 (K211R) showed significantly higher proliferation and invasion than those transfected with FLOT2 (WT). CONCLUSIONS: The K211 site of FLOT2 undergoes acetylation modification, and HDAC6 mediates deacetylation at this site, inhibiting proteasomal degradation of FLOT2 and maintaining its stability and tumor-promoting function in nasopharyngeal carcinoma.

Asunto(s)

Histona Desacetilasa 6 , Proteínas de la Membrana , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Acetilación , Línea Celular Tumoral , Proliferación Celular , Células HEK293 , Histona Desacetilasa 6/metabolismo , Histona Desacetilasa 6/genética , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Lisina/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Mutación , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/genética , Niacinamida/farmacología , Procesamiento Proteico-Postraduccional

RESUMEN

Nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD+), has robust cognitive benefits and alleviates neuroinflammation in Alzheimer's Disease (AD) mouse models without decreasing beta-amyloid plaque pathology. Such effects may be mediated by the reactive species interactome (RSI), at the metabolome level. In this study, we employed in vitro and in vivo models of oxidative stress, aging and AD to profile the effects of NR on neuronal survival, RSI, and the whole proteome characterization of cortex and hippocampus. RSI analysis yielded a complex modulation upon NR treatment. We constructed protein co-expression networks and correlated them to NR treatment and all measured reactive species. We observed brain-area specific effects of NR on co-expressed protein modules of oxidative phosphorylation, fatty acid oxidation, and neurotransmitter regulation pathways, which correlated with RSI components. The current study contributes to the understanding of modulation of the metabolome, specifically after NR treatment in AD and how it may play disease-modifying roles.

Asunto(s)

Enfermedad de Alzheimer , Encéfalo , Metabolismo Energético , Niacinamida , Compuestos de Piridinio , Animales , Niacinamida/análogos & derivados , Niacinamida/farmacología , Ratones , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Enfermedad de Alzheimer/metabolismo , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/fisiología , Proteómica , Proteoma/metabolismo , Proteoma/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Ratones Endogámicos C57BL , Masculino , Especies Reactivas de Oxígeno/metabolismo , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Neuronas/metabolismo , Neuronas/efectos de los fármacos

RESUMEN

Paclitaxel (PTX) is a microtubule stabilizer that disrupts the normal cycle of microtubule depolymerization and repolymerization, leading to cell cycle arrest and cancer cell death. It is commonly used as a first-line chemotherapeutics for various malignancies, such as breast cancer, non-small cell lung cancer, and ovarian cancer. However, PTX chemotherapy is associated with common and serious side effects, including chemotherapy-induced peripheral neuropathy (CIPN). As cancer treatment advances and survival rates increase, the impact of CIPN on patients' quality of life has become more significant. To date, there is no effective treatment strategy for CIPN. Surtuin3 (SIRT3) is a nicotinamide adenine dinucleotide (NAD+) dependent protein deacetylase located on mitochondria. It transfers the acetyl group of the lysine side chain of acetylated substrate proteins to NAD+, producing deacetylated proteins to regulate mitochondrial energy metabolic processes. SIRT3 has been found to play an important role in various diseases, including aging, neurodegenerative diseases, cancer, heart disease, metabolic diseases, etc. However, the role of SIRT3 in CIPN is still unknown. This study found for the first time that activating SIRT3 helps to improve paclitaxel-induced CIPN. Nicotinamide riboside (NR) can protect dorsal root ganglion (DRG) mitochondria against oxidative damage caused by paclitaxel through activating SIRT3-MnSOD2 and SIRT3-Nrf2 pathway. Moreover, NR can enhance the anticancer activity of paclitaxel. Together, our research provides new strategy and candidate drug for the treatment of CIPN.

Asunto(s)

Niacinamida , Paclitaxel , Enfermedades del Sistema Nervioso Periférico , Compuestos de Piridinio , Sirtuina 3 , Paclitaxel/toxicidad , Sirtuina 3/metabolismo , Animales , Compuestos de Piridinio/farmacología , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/prevención & control , Enfermedades del Sistema Nervioso Periférico/metabolismo , Niacinamida/análogos & derivados , Niacinamida/farmacología , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/toxicidad , Ratones , Humanos , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Masculino

RESUMEN

This study investigated the antioxidant and neuroprotective effects of nicotinamide combined with ischemic preconditioning against cerebral ischemia reperfusion (CIR) injury. Thirty-five Wistar albino male rats were randomly divided into five groups: sham, preconditioned ischemia/reperfusion (IP+IR), ischemia/reperfusion (IR), preconditioned ischemia/reperfusion + nicotinamide (IP+IR+N), and ischemia/reperfusion + nicotinamide (IR+N). CIR was achieved with bilateral common carotid artery occlusion. IP+IR and IP+IR+N groups 30 min before ischemia; Three cycles of 10 sec ischemia/30 sec reperfusion followed by 20 min IR were applied. The IP+IR+N and IR+N groups received 500 mg/kg nicotinamide intraperitoneally. After 24 h of reperfusion, a neurological evaluation was performed and vertical pole test. Biochemically, malondialdehyde (MDA), glutathione (GSH) levels and catalase (CAT) activity were measured in blood and brain tissue samples. Rates of red neurons, sateliosis and spongiosis were determined histopathologically in the prefrontal cortex areas. After CIR, MDA levels increased significantly in serum and brain tissue in the IR group compared to the sham group, while GSH and CAT activity decreased in the brain tissue (p < 0.05). MDA levels in the tissues were found significantly decreased in the IR+N group compared to the IR group (p < 0.05). Administration of nicotinamide together with IP significantly decreased MDA levels in brain tissue and increased GSH and CAT activity (p < 0.05). Compared to the IR group, the morphological and neurological damage in the prefrontal cortex areas decreased in the IP+IR, IP+IR+N, and IR+N groups (p < 0.05). In addition, red neuron, sateliosis and spongiosis rates increased significantly in the IR group compared to the Sham, IP+IR+N, IR+N groups (p < 0.001 for all). In neurological evaluation, while the neurological score increased and the time on the vertical pole decreased significantly in the IR group, preconditioning, and nicotinamide groups reversed (p < 0.05). The study's results show that nicotinamide administration with ischemic preconditioning alleviates cerebral ischemia/reperfusion injury.

Asunto(s)

Isquemia Encefálica , Precondicionamiento Isquémico , Fármacos Neuroprotectores , Niacinamida , Ratas Wistar , Daño por Reperfusión , Animales , Daño por Reperfusión/prevención & control , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Niacinamida/farmacología , Niacinamida/uso terapéutico , Masculino , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Precondicionamiento Isquémico/métodos , Isquemia Encefálica/prevención & control , Isquemia Encefálica/metabolismo , Malondialdehído/metabolismo , Glutatión/metabolismo , Ratas , Catalasa/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Antioxidantes/farmacología , Antioxidantes/uso terapéutico

RESUMEN

A compromised capacity to maintain NAD pools is recognized as a key underlying pathophysiological feature of neurodegenerative diseases. NAD acts as a substrate in major cell functions including mitochondrial homeostasis, cell signalling, axonal transport, axon/Wallerian degeneration, and neuronal energy supply. Dendritic degeneration is an early marker of neuronal stress and precedes cell loss. However, little is known about dendritic structural preservation in pathologic environments and remodelling in mature neurons. Retinal ganglion cell dendritic atrophy is an early pathological feature in animal models of the disease and has been demonstrated in port-mortem human glaucoma samples. Here we report that a nicotinamide (a precursor to NAD through the NAD salvage pathway) enriched diet provides robust retinal ganglion cell dendritic protection and preserves dendritic structure in a rat model of experimental glaucoma. Metabolomic analysis of optic nerve samples from the same animals demonstrates that nicotinamide provides robust metabolic neuroprotection in glaucoma. Advances in our understanding of retinal ganglion cell metabolic profiles shed light on the energetic shift that triggers early neuronal changes in neurodegenerative diseases. As nicotinamide can improve visual function short term in existing glaucoma patients, we hypothesize that a portion of this visual recovery may be due to dendritic preservation in stressed, but not yet fully degenerated, retinal ganglion cells.

Asunto(s)

Modelos Animales de Enfermedad , Glaucoma , Fármacos Neuroprotectores , Niacinamida , Células Ganglionares de la Retina , Animales , Niacinamida/farmacología , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/patología , Células Ganglionares de la Retina/metabolismo , Glaucoma/metabolismo , Glaucoma/patología , Fármacos Neuroprotectores/farmacología , Ratas , Relación Dosis-Respuesta a Droga , Masculino , Administración Oral , Nervio Óptico/efectos de los fármacos , Nervio Óptico/patología , Nervio Óptico/metabolismo , Neuroprotección/efectos de los fármacos , Neuroprotección/fisiología , Dendritas/efectos de los fármacos , Dendritas/patología , Dendritas/metabolismo , Complejo Vitamínico B/farmacología , Complejo Vitamínico B/administración & dosificación

RESUMEN

Nicotinamide, known as Vitamin-B3, has shown promising potential in improving various medical conditions. Carbacylamidophosphates (CAPh) are versatile phosphoramide ligands with a wide range of applications in both biochemistry and chemistry. Herein, to obtain compounds with enhanced anticancer activity and study the effect of the structure on this activity, four new Co(II) complexes of vitaminB3-based CAPh ligands with the formula of CoCl2[3-NC5H4CONHPO(NC5H10)2]2(C1), CoCl2[3-NC5H4CONHPO(NC5H9CH3)2]2(C2), CoCl2[3-NC5H4CONHPO(NC6H12)2]2(C3), and CoCl2[3-NC5H4CONHPO(NC4H10)2]2(C4) were designed and synthesized. FT-IR, UV-Vis, Atomic Absorption (AAS),1H, 13C, and 31PNMR, and Mass spectroscopies beside CHN and Molar conductivity methods were utilized to characterize the synthesized compounds. Using MTT-assay and Flow Cytometry, the anticancer effects of these complexes were studied on three distinct cell lines, including one normal cell line (MCF10A) and two cancer cell lines (MDA-MB-231, MCF-7). Results showed that our ligands could form complexes by coordinating with cobalt, which, not only have a very strong killing effect on cancer cells but also have a higher level of safety for normal cells and are more cost-efficient than Cisplatin. C3 was the most effective complex at inhibiting the growth of MCF-7 and MDA-MB-231 cells which exhibited a remarkable 97.5 % reduction in cancer cell growth and a Selectivity Index up to > 37. This is an impressive 93 and 54 times more selective and safer than commonly used drugs like Cisplatin and Doxorubicin, respectively.Flow Cytometry analysis shows complex-induced breast cancer cell apoptosis.The ligands' amine structure and ring size can directly impact the complexes' anticancer effect and safety for normal cells.

Asunto(s)

Antineoplásicos , Proliferación Celular , Cobalto , Complejos de Coordinación , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Amidas/química , Amidas/farmacología , Amidas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cobalto/química , Cobalto/farmacología , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Ligandos , Estructura Molecular , Relación Estructura-Actividad , Niacinamida/química , Niacinamida/farmacología

RESUMEN

It has been well acknowledged that maternal exposure to fine particulate matters (PM2.5) might lead to poor pregnancy outcomes including the intrauterine growth restriction (IUGR) by interfering with the placental development. Our previous studies have demonstrated that maternal PM2.5 exposure induces IUGR, accompanied with increased maternal circulating TNFα level and impaired extravillous trophoblast cells (EVTs) invasion in mice. In this study, HTR8/SVneo cells, the immortalized human EVTs line, were used to assess effects and the underlying molecular mechanisms of nicotinamide on the impaired EVTs invasion. Our results showed that, the placental FLT1 protein level was significantly increased whereas maternal serum nicotinamide concentration was remarkably decreased in PM2.5-exposured pregnant mice at GD17.5 (vaginal plug day=GD0.5), compared to that in normal GD17.5 pregnant mice. FLT1 expression in HTR8/SVneo cells was significantly up-regulated by TNFα treatment, and the down-regulated FLT1 expression effectively abated the inhibitory effects of TNFα on HTR8/SVneo cells migration and invasion. Meanwhile, TNFα promoted reactive oxygen species (ROS) production and NF-κB signaling pathway activation in HTR8/SVneo cells in a dose-dependent manner. Nicotinamide treatment significantly reversed the effects of TNFα on cell migration and invasion, as well as the FLT1 expression, ROS production and NF-κB pathway activation. In summary, increased TNFα induced by PM2.5 exposure inhibits EVTs invasion by activating the ROS/NF-κB/FLT1 signaling pathway, and this adverse effect could be attenuated by nicotinamide treatment, suggesting a potential application in the clinical intervention of PM2.5-induced IUGR.

Asunto(s)

FN-kappa B , Niacinamida , Material Particulado , Especies Reactivas de Oxígeno , Trofoblastos , Factor de Necrosis Tumoral alfa , Receptor 1 de Factores de Crecimiento Endotelial Vascular , Trofoblastos/efectos de los fármacos , Trofoblastos/patología , Niacinamida/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Material Particulado/toxicidad , Femenino , Animales , Especies Reactivas de Oxígeno/metabolismo , FN-kappa B/metabolismo , Embarazo , Ratones , Humanos , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Movimiento Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Línea Celular , Contaminantes Atmosféricos/toxicidad , Exposición Materna/efectos adversos , Trofoblastos Extravellosos

RESUMEN

Thioredoxin Reductase (TrxR) functions to recycle thioredoxin (Trx) during hydroperoxide metabolism mediated by peroxiredoxins and is currently being targeted using the FDA-approved anti-rheumatic drug, auranofin (AF), to selectively sensitize cancer cells to therapy. AF treatment decreased TrxR activity and clonogenic survival in small cell lung cancer (SCLC) cell lines (DMS273 and DMS53) as well as the H727 atypical lung carcinoid cell line. AF treatment also significantly sensitized DMS273 and H727 cell lines in vitro to sorafenib, an FDA-approved multi-kinase inhibitor that depleted intracellular glutathione (GSH). The pharmacokinetic, pharmacodynamic, and safety profile of AF was examined in nude mice with DMS273 xenografts administered AF intraperitoneally at 2 mg/kg or 4 mg/kg (IP) once (QD) or twice daily (BID) for 1-5 d. Plasma levels of AF were 10-20 µM (determined by mass spectrometry of gold), and the optimal inhibition of TrxR activity was obtained at 4 mg/kg once daily, with no effect on glutathione peroxidase 1 activity. This AF treatment extended for 14 d, inhibited TrxR (>75%), and resulted in a significant prolongation of median overall survival from 19 to 23 d (p = .04, N = 30 controls, 28 AF). In this experiment, there were no observed changes in animal bodyweight, complete blood counts (CBCs), bone marrow toxicity, blood urea nitrogen, or creatinine. These results support the hypothesis that AF effectively inhibits TrxR both in vitro and in vivo in SCLC, sensitizes NETs and SCLC to sorafenib, and could be repurposed as an adjuvant therapy with targeted agents that induce disruptions in thiol metabolism.

Asunto(s)

Auranofina , Neoplasias Pulmonares , Compuestos de Fenilurea , Carcinoma Pulmonar de Células Pequeñas , Sorafenib , Reductasa de Tiorredoxina-Disulfuro , Ensayos Antitumor por Modelo de Xenoinjerto , Auranofina/farmacología , Auranofina/uso terapéutico , Animales , Sorafenib/farmacología , Sorafenib/uso terapéutico , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidores , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Humanos , Ratones , Línea Celular Tumoral , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/uso terapéutico , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/metabolismo , Ratones Desnudos , Niacinamida/análogos & derivados , Niacinamida/farmacología , Niacinamida/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico

RESUMEN

Nicotinamide riboside (NR), a NAD+ precursor, has received attention due to several health benefits it has induced in experimental models. Studies in cultured cells, animals, and humans consistently show increased NAD+ availability after NR supplementation, which is considered the only mode of NR action that leads to health benefits. In the present study, we show that a persistently low NR concentration (1 µM) in the growth medium of BEAS-2B human cells, grown in a monolayer, induces energy stress, which precedes a cellular NAD+ increase after 192 h. NR concentrations greater than 1 µM under the specified conditions were cytotoxic in the 2D cell culture model, while all concentrations tested in the 3D cell culture model (BEAS-2B cell spheroids exposed to 1, 5, 10, and 50 µM NR) induced apoptosis. Shotgun proteomics revealed that NR modulated the abundance of proteins, agreeing with the observed effects on cellular energy metabolism and cell growth or survival. Energy stress may activate pathways that lead to health benefits such as cancer prevention. Accordingly, the premalignant 1198 cell line was more sensitive to NR cytotoxicity than the phenotypically normal parent BEAS-2B cell line. The role of a mild energy stress induced by low concentrations of NR in its beneficial effects deserves further investigation. On the other hand, strategies to increase the bioavailability of NR require attention to toxic effects that may arise.

Asunto(s)

Metabolismo Energético , Niacinamida , Compuestos de Piridinio , Humanos , Niacinamida/análogos & derivados , Niacinamida/farmacología , Compuestos de Piridinio/farmacología , Metabolismo Energético/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Línea Celular , Apoptosis/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Proliferación Celular/efectos de los fármacos , Reprogramación Metabólica

RESUMEN

HIV disease remains prevalent in the United States and is particularly prevalent in sub-Saharan Africa. Recent investigations revealed that mitochondrial dysfunction in kidney contributes to HIV-associated nephropathy (HIVAN) in Tg26 transgenic mice. We hypothesized that nicotinamide adenine dinucleotide (NAD) deficiency contributes to energetic dysfunction and progressive tubular injury. We investigated metabolomic mechanisms of HIVAN tubulopathy. Tg26 and wild-type (WT) mice were treated with the farnesoid X receptor (FXR) agonist INT-747 or nicotinamide riboside (NR) from 6 to 12 wk of age. Multiomic approaches were used to characterize kidney tissue transcriptomes and metabolomes. Treatment with INT-747 or NR ameliorated kidney tubular injury, as shown by serum creatinine, the tubular injury marker urinary neutrophil-associated lipocalin, and tubular morphometry. Integrated analysis of metabolomic and transcriptomic measurements showed that NAD levels and production were globally downregulated in Tg26 mouse kidneys, especially nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD salvage pathway. Furthermore, NAD-dependent deacetylase sirtuin3 activity and mitochondrial oxidative phosphorylation activity were lower in ex vivo proximal tubules from Tg26 mouse kidneys compared with those of WT mice. Restoration of NAD levels in the kidney improved these abnormalities. These data suggest that NAD deficiency might be a treatable target for HIVAN.NEW & NOTEWORTHY The study describes a novel investigation that identified nicotinamide adenine dinucleotide (NAD) deficiency in a widely used HIV-associated nephropathy (HIVAN) transgenic mouse model. We show that INT-747, a farnesoid X receptor agonist, and nicotinamide riboside (NR), a precursor of nicotinamide, each ameliorated HIVAN tubulopathy. Multiomic analysis of mouse kidneys revealed that NAD deficiency was an upstream metabolomic mechanism contributing to HIVAN tubulopathy.

Asunto(s)

Nefropatía Asociada a SIDA , Ratones Transgénicos , NAD , Niacinamida , Compuestos de Piridinio , Sirtuina 3 , Animales , NAD/metabolismo , Nefropatía Asociada a SIDA/metabolismo , Nefropatía Asociada a SIDA/genética , Nefropatía Asociada a SIDA/patología , Niacinamida/análogos & derivados , Niacinamida/farmacología , Compuestos de Piridinio/farmacología , Sirtuina 3/metabolismo , Sirtuina 3/genética , Sirtuina 3/deficiencia , Modelos Animales de Enfermedad , Nicotinamida Fosforribosiltransferasa/metabolismo , Nicotinamida Fosforribosiltransferasa/genética , Ratones , Mitocondrias/metabolismo , Mitocondrias/patología , Progresión de la Enfermedad , Metabolómica , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/deficiencia , Riñón/metabolismo , Riñón/patología , Riñón/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Citocinas/metabolismo

RESUMEN

Hesperidin (HSP) is a natural flavonoid glycoside with very low aqueous solubility and a slow dissolution rate, limiting its effectiveness. This study aims to address these issues by creating co-crystals of hesperidin with water-soluble small molecules (co-formers) such as L-arginine, glutathione, glycine, and nicotinamide. Using the solvent drop grinding method, we prepared three different molar ratios of hesperidin to co-formers (1:1, 1:3, and 1:5) and conducted in-vitro solubility and dissolution studies. The results demonstrated that the prepared co-crystals exhibited significantly enhanced solubility and dissolution rates compared to untreated hesperidin. Of particular note, the HSP co-crystals formula (HSP: L-arg 1:5) displayed approximately 4.5 times higher dissolution than pure hesperidin. Further analysis using FTIR, powder x-ray diffraction patterns, and DSC thermograms validated the formation of co-crystals between HSP and L-arginine. Additionally, co-crystallization with L-arginine improved the in vitro anti-inflammatory and antioxidant activities of hesperidin compared to the untreated drug. This study highlights the potential of using water-soluble small molecules (co-formers) through co-crystallization to enhance the solubility, dissolution, and biological activities of poorly water-soluble drugs. Furthermore, in vivo studies are crucial to validate these promising results.

Asunto(s)

Antiinflamatorios , Antioxidantes , Arginina , Cristalización , Hesperidina , Solubilidad , Hesperidina/química , Hesperidina/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Antiinflamatorios/química , Antiinflamatorios/farmacología , Arginina/química , Glutatión/química , Niacinamida/química , Niacinamida/farmacología , Glicina/química , Animales , Agua/química , Difracción de Rayos X/métodos , Ratones