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1.
Molecules ; 26(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34361546

RESUMO

The adsorption of retinol, niacinamide and glycolic acid active ingredients on the internal surface of halloysite in an aqueous environment was explored at the molecular level by means of calculations based on quantum mechanics and force fields from empirical interatomic potentials. These active ingredients are stably adsorbed on the internal surface of halloysite forming hydrogen bonds between the hydrogen, oxygen and nitrogen atoms with the hydroxyl groups of the inner surface of the halloysite. In addition, electrostatic interaction between these active ingredients with the water molecules was observed. Therefore, the theoretical results indicate that the adsorption of these active principles is favourable in the halloysite nanotube, which allows directing future experimental investigations for the development and design of retinol, niacinamide and glycolic acid with halloysite nanotubes systems, which may be topical formulations for skincare.


Assuntos
Argila/química , Glicolatos , Niacinamida , Higiene da Pele , Vitamina A , Administração Tópica , Glicolatos/química , Glicolatos/farmacologia , Humanos , Niacinamida/química , Niacinamida/farmacologia , Vitamina A/química , Vitamina A/farmacologia
2.
Nat Commun ; 12(1): 4662, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34341345

RESUMO

Impaired cellular cholesterol efflux is a key factor in the progression of renal, cardiovascular, and autoimmune diseases. Here we describe a class of 5-arylnicotinamide compounds, identified through phenotypic drug discovery, that upregulate ABCA1-dependent cholesterol efflux by targeting Oxysterol Binding Protein Like 7 (OSBPL7). OSBPL7 was identified as the molecular target of these compounds through a chemical biology approach, employing a photoactivatable 5-arylnicotinamide derivative in a cellular cross-linking/immunoprecipitation assay. Further evaluation of two compounds (Cpd A and Cpd G) showed that they induced ABCA1 and cholesterol efflux from podocytes in vitro and normalized proteinuria and prevented renal function decline in mouse models of proteinuric kidney disease: Adriamycin-induced nephropathy and Alport Syndrome. In conclusion, we show that small molecule drugs targeting OSBPL7 reveal an alternative mechanism to upregulate ABCA1, and may represent a promising new therapeutic strategy for the treatment of renal diseases and other disorders of cellular cholesterol homeostasis.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Colesterol/metabolismo , Nefropatias Diabéticas/metabolismo , Compostos Orgânicos/farmacologia , Podócitos/metabolismo , Proteinúria/metabolismo , Receptores de Esteroides/antagonistas & inibidores , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Transporte Biológico/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células HEK293 , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Camundongos da Linhagem 129 , Camundongos Knockout , Estrutura Molecular , Niacinamida/química , Niacinamida/farmacologia , Compostos Orgânicos/síntese química , Compostos Orgânicos/química , Podócitos/citologia , Interferência de RNA , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Células THP-1
3.
J Evid Based Integr Med ; 26: 2515690X211036875, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34384258

RESUMO

Worldwide, the turmoil of the SARS-CoV-2 (COVID-19) pandemic has generated a burst of research efforts in search of effective prevention and treatment modalities. Current recommendations on natural supplements arise from mostly anecdotal evidence in other viral infections and expert opinion, and many clinical trials are ongoing. Here the authors review the evidence and rationale for the use of natural supplements for prevention and treatment of COVID-19, including those with potential benefit and those with potential harms. Specifically, the authors review probiotics, dietary patterns, micronutrients, antioxidants, polyphenols, melatonin, and cannabinoids. Authors critically evaluated and summarized the biomedical literature published in peer-reviewed journals, preprint servers, and current guidelines recommended by expert scientific governing bodies. Ongoing and future trials registered on clinicaltrials.gov were also recorded, appraised, and considered in conjunction with the literature findings. In light of the controversial issues surrounding the manufacturing and marketing of natural supplements and limited scientific evidence available, the authors assessed the available data and present this review to equip clinicians with the necessary information regarding the evidence for and potential harms of usage to promote open discussions with patients who are considering dietary supplements to prevent and treat COVID-19.


Assuntos
Antioxidantes/uso terapêutico , COVID-19/tratamento farmacológico , Suplementos Nutricionais , Micronutrientes/uso terapêutico , Extratos Vegetais/uso terapêutico , Antioxidantes/farmacologia , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Humanos , Melatonina/farmacologia , Melatonina/uso terapêutico , Micronutrientes/farmacologia , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Probióticos/uso terapêutico , SARS-CoV-2
4.
Am J Physiol Heart Circ Physiol ; 321(2): H400-H411, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34213392

RESUMO

Therapeutic agents that increase the Hb affinity for oxygen (O2) could, in theory, lead to decreased O2 release from Hb and impose a hypoxic risk to tissues. In this study, GBT1118, an allosteric modifier of Hb affinity for O2, was used to assess the impact of increasing Hb affinity for O2 on brain tissue oxygenation, blood pressure, heart rate, O2 delivery, and tolerance to hypoxia in Townes transgenic sickle cell disease (SCD) mice. Brain oxygenation and O2 delivery were studied during normoxia and severe hypoxic challenges. Chronic treatment with GBT1118 increased Hb affinity for O2, reducing the Po2 for 50% HbO2 saturation (P50) in SCD mice from 31 mmHg to 18 mmHg. This treatment significantly reduced anemia, increasing hematocrit by 33%, improved cardiac output (CO), and O2 delivery and extraction. Chronically increasing Hb affinity for O2 with GBT1118 preserved cortical O2 tension during normoxia, improved cortical O2 tension during hypoxia, and increased tolerance to severe hypoxia in SCD mice. Independent of hematological changes induced by chronic treatment, a single dose of GBT1118 significantly improved tolerance to hypoxia, highlighting the benefits of increasing Hb affinity for O2 and consequently reducing sickling of RBCs in blood during hypoxia in SCD.NEW & NOTEWORTHY Chronic pharmacologically increased hemoglobin affinity for oxygen in sickle cell disease mice alleviated hematological consequences of sickle cell disease, increasing RBC half-life, hematocrit, and hemoglobin concentration, while also decreasing reticulocyte count. Additionally, chronically increased hemoglobin affinity for oxygen significantly improved survival as well as cortical tissue oxygenation in sickle cell disease mice during hypoxia, suggesting that oxygen delivery and utilization is improved by increased hemoglobin affinity for oxygen.


Assuntos
Anemia Falciforme/metabolismo , Benzaldeídos/farmacologia , Córtex Cerebral/metabolismo , Eritrócitos/efeitos dos fármacos , Fármacos Hematológicos/farmacologia , Hemoglobina Falciforme/efeitos dos fármacos , Hipóxia/metabolismo , Niacinamida/análogos & derivados , Oxigênio/metabolismo , Regulação Alostérica , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Hematócrito , Hemoglobina Falciforme/metabolismo , Camundongos , Camundongos Transgênicos , Niacinamida/farmacologia , Pressão Parcial
5.
Eur J Med Chem ; 223: 113663, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198150

RESUMO

Acetylcholinesterase (AChE) inhibitors are currently the first-line drugs approved by the FDA for the treatment of Alzheimer's disease (AD). However, a short effective-window limits their therapeutic benefits. Clinical studies have confirmed that the combination of AChE inhibitors and neuroprotective agents exhibits better anti-AD effects. We have previously reported that the dual AChE/GSK3ß (Glycogen synthase kinase 3ß) modulators have both neuroprotective effects and cognitive impairment-improvement effects. In this study, we characterized a new backbone of the AChE/GSK3ß inhibitor 11c. It was identified as a highly potent AChE inhibitor and was found superior to donepezil, the first-line drug for the treatment of AD. In vivo studies confirmed that 11c significantly inhibited the activity of AChE in the brain but had little effect on the activity of AChE in the intestine. This advantage of 11c was expected to reduce the peripheral side effects caused by donepezil. Furthermore, biomarker studies have shown that 11c also improved the levels of acetylcholine and synaptophysin in the brain and exhibited neuroprotective effects. Preliminary in vivo and in vitro research results underline the exciting potential of compound 11c in the treatment of AD.


Assuntos
Acetilcolina/metabolismo , Acetilcolinesterase/química , Encéfalo/metabolismo , Inibidores da Colinesterase/química , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Niacinamida/química , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Animais , Sítios de Ligação , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Desenho de Fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Intestinos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Simulação de Dinâmica Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Niacinamida/metabolismo , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade , Regulação para Cima/efeitos dos fármacos
6.
Biomed Pharmacother ; 141: 111823, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34147902

RESUMO

Here, we demonstrate that the two distinct formulations of our anti-sepsis drug candidate Rejuveinix (RJX), have a very favorable safety profile in Wistar Albino rats at dose levels comparable to the projected clinical dose levels. 14-day treatment with RJX-P (RJX PPP.18.1051) or RJX-B (RJX-B200702-CLN) similarly elevated the day 15 tissue levels of the antioxidant enzyme superoxide dismutase (SOD) as well as ascorbic acid in both the lungs and liver in a dose-dependent fashion. The activity of SOD and ascorbic acid levels were significantly higher in tissues of RJX-P or RJX-B treated rats than vehicle-treated control rats (p < 0.0001). There was no statistically significant difference between tissue SOD activity or ascorbic acid levels of rats treated with RJX-P vs. rats treated with RJX-B (p > 0.05). The observed elevations of the SOD and ascorbic acid levels were transient and were no longer detectable on day 28 following a 14-day recovery period. These results demonstrate that RJX-P and RJX-B are bioequivalent relative to their pharmacodynamic effects on tissue SOD and ascorbic acid levels. Furthermore, both formulations showed profound protective activity in a mouse model of sepsis. In agreement with the PD evaluations in rats and their proposed mechanism of action, both RJX-P and RJX-B exhibited near-identical potent and dose-dependent anti-oxidant and anti-inflammatory activity in the LPS-GalN model of ARDS and multi-organ failure in mice.


Assuntos
Ácido Ascórbico/química , Ácido Ascórbico/uso terapêutico , Sulfato de Magnésio/química , Sulfato de Magnésio/uso terapêutico , Niacinamida/química , Niacinamida/uso terapêutico , Ácido Pantotênico/química , Ácido Pantotênico/uso terapêutico , Piridoxina/química , Piridoxina/uso terapêutico , Riboflavina/química , Riboflavina/uso terapêutico , Sepse/tratamento farmacológico , Sepse/metabolismo , Tiamina/química , Tiamina/uso terapêutico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Ácido Ascórbico/farmacologia , Cães , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Composição de Medicamentos , Feminino , Humanos , Lipopolissacarídeos/toxicidade , Sulfato de Magnésio/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Niacinamida/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ácido Pantotênico/farmacologia , Piridoxina/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Riboflavina/farmacologia , Sepse/patologia , Superóxido Dismutase/metabolismo , Tiamina/farmacologia
7.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069373

RESUMO

Despite liver cancer being the second-leading cause of cancer-related death worldwide, few systemic drugs have been approved. Sorafenib, the first FDA-approved systemic drug for unresectable hepatocellular carcinoma (HCC), is limited by resistance. However, the precise mechanisms underlying this phenomenon are unknown. Since fibrinogen-like 1 (FGL1) is involved in HCC progression and upregulated after anticancer therapy, we investigated its role in regulating sorafenib resistance in HCC. FGL1 expression was assessed in six HCC cell lines (HepG2, Huh7, Hep3B, SNU387, SNU449, and SNU475) using western blotting. Correlations between FGL1 expression and sorafenib resistance were examined by cell viability, colony formation, and flow cytometry assays. FGL1 was knocked-down to confirm its effects on sorafenib resistance. FGL1 expression was higher in HepG2, Huh7, and Hep3B cells than in SNU387, SNU449, and SNU475 cells; high FGL1-expressing HCC cells showed a lower IC50 and higher sensitivity to sorafenib. In Huh7 and Hep3B cells, FGL1 knockdown significantly increased colony formation by 61% (p = 0.0013) and 99% (p = 0.0002), respectively, compared to that in controls and abolished sorafenib-induced suppression of colony formation, possibly by modulating ERK and autophagy signals. Our findings demonstrate that sorafenib resistance mediated by FGL1 in HCC cells, suggesting FGL1 as a potential sorafenib-resistance biomarker and target for HCC therapy.


Assuntos
Carcinoma Hepatocelular/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Fibrinogênio/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Fibrinogênio/fisiologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Neoplasias Hepáticas/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Niacinamida/farmacologia , Compostos de Fenilureia/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Sorafenibe/metabolismo , Sorafenibe/farmacologia
8.
Am J Physiol Heart Circ Physiol ; 321(2): H353-H368, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34142887

RESUMO

Arterial stiffness, a consequence of smoking, is an underlying risk factor of cardiovascular diseases. Epoxyeicosatrienoic acids (EETs), hydrolyzed by soluble epoxide hydrolase (sEH), have beneficial effects against vascular dysfunction. However, the role of sEH knockout in nicotine-induced arterial stiffness was not characterized. We hypothesized that sEH knockout could prevent nicotine-induced arterial stiffness. In the present study, Ephx2 (the gene encodes sEH enzyme) null (Ephx2-/-) mice and wild-type (WT) littermate mice were infused with or without nicotine and administered with or without nicotinamide [NAM, sirtuin-1 (SIRT1) inhibitor] simultaneously for 4 wk. Nicotine treatment increased sEH expression and activity in the aortas of WT mice. Nicotine infusion significantly induced vascular remodeling, arterial stiffness, and SIRT1 deactivation in WT mice, which was attenuated in Ephx2 knockout mice (Ephx2-/- mice) without NAM treatment. However, the arterial protective effects were gone in Ephx2-/- mice with NAM treatment. In vitro, 11,12-EET treatment attenuated nicotine-induced matrix metalloproteinase 2 (MMP2) upregulation via SIRT1-mediated yes-associated protein (YAP) deacetylation. In conclusion, sEH knockout attenuated nicotine-induced arterial stiffness and vascular remodeling via SIRT1-induced YAP deacetylation.NEW & NOTEWORTHY We presently show that sEH knockout repressed nicotine-induced arterial stiffness and extracellular matrix remodeling via SIRT1-induced YAP deacetylation, which highlights that sEH is a potential therapeutic target in smoking-induced arterial stiffness and vascular remodeling.


Assuntos
Aorta/efeitos dos fármacos , Epóxido Hidrolases/genética , Niacinamida/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Sirtuína 1/metabolismo , Rigidez Vascular/efeitos dos fármacos , Complexo Vitamínico B/farmacologia , Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Aorta/metabolismo , Aorta/fisiopatologia , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 2 da Matriz/genética , Camundongos , Camundongos Knockout , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/efeitos dos fármacos , Rigidez Vascular/genética , Vasodilatadores/farmacologia
9.
Cell Death Dis ; 12(7): 651, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172715

RESUMO

Alzheimer's disease is the most common age-related neurodegenerative disorder. Familial forms of Alzheimer's disease associated with the accumulation of a toxic form of amyloid-ß (Aß) peptides are linked to mitochondrial impairment. The coenzyme nicotinamide adenine dinucleotide (NAD+) is essential for both mitochondrial bioenergetics and nuclear DNA repair through NAD+-consuming poly (ADP-ribose) polymerases (PARPs). Here we analysed the metabolomic changes in flies overexpressing Aß and showed a decrease of metabolites associated with nicotinate and nicotinamide metabolism, which is critical for mitochondrial function in neurons. We show that increasing the bioavailability of NAD+ protects against Aß toxicity. Pharmacological supplementation using NAM, a form of vitamin B that acts as a precursor for NAD+ or a genetic mutation of PARP rescues mitochondrial defects, protects neurons against degeneration and reduces behavioural impairments in a fly model of Alzheimer's disease. Next, we looked at links between PARP polymorphisms and vitamin B intake in patients with Alzheimer's disease. We show that polymorphisms in the human PARP1 gene or the intake of vitamin B are associated with a decrease in the risk and severity of Alzheimer's disease. We suggest that enhancing the availability of NAD+ by either vitamin B supplements or the inhibition of NAD+-dependent enzymes such as PARPs are potential therapies for Alzheimer's disease.


Assuntos
Doença de Alzheimer/genética , Proteínas de Drosophila/genética , Mitocôndrias/genética , Mutação , NAD/metabolismo , Neurônios/enzimologia , Poli(ADP-Ribose) Polimerase-1/genética , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Animais Geneticamente Modificados , Comportamento Animal , Modelos Animais de Doenças , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Humanos , Metaboloma , Metabolômica , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , Mitocôndrias/ultraestrutura , Atividade Motora , Degeneração Neural , Neurônios/efeitos dos fármacos , Neurônios/patologia , Niacinamida/farmacologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Polimorfismo de Nucleotídeo Único
10.
Nutrients ; 13(5)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34068917

RESUMO

Nicotinamide adenine dinucleotide (NAD) is an essential redox cofactor, but it also acts as a substrate for NAD-consuming enzymes, regulating cellular events such as DNA repair and gene expression. Since such processes are fundamental to support cancer cell survival and proliferation, sustained NAD production is a hallmark of many types of neoplasms. Depleting intratumor NAD levels, mainly through interference with the NAD-biosynthetic machinery, has emerged as a promising anti-cancer strategy. NAD can be generated from tryptophan or nicotinic acid. In addition, the "salvage pathway" of NAD production, which uses nicotinamide, a byproduct of NAD degradation, as a substrate, is also widely active in mammalian cells and appears to be highly exploited by a subset of human cancers. In fact, research has mainly focused on inhibiting the key enzyme of the latter NAD production route, nicotinamide phosphoribosyltransferase (NAMPT), leading to the identification of numerous inhibitors, including FK866 and CHS-828. Unfortunately, the clinical activity of these agents proved limited, suggesting that the approaches for targeting NAD production in tumors need to be refined. In this contribution, we highlight the recent advancements in this field, including an overview of the NAD-lowering compounds that have been reported so far and the related in vitro and in vivo studies. We also describe the key NAD-producing pathways and their regulation in cancer cells. Finally, we summarize the approaches that have been explored to optimize the therapeutic response to NAMPT inhibitors in cancer.


Assuntos
Antineoplásicos/farmacologia , NAD/biossíntese , NAD/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Vias Biossintéticas , Morte Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Citocinas , Dano ao DNA , Reparo do DNA , Humanos , Niacina/farmacologia , Niacinamida/farmacologia , Nicotinamida Fosforribosiltransferase , Estresse Oxidativo
11.
Stem Cell Res Ther ; 12(1): 362, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172095

RESUMO

BACKGROUND: Vitamin B3 (nicotinamide) plays important roles in metabolism as well as in SIRT and PARP pathways. It is also recently reported as a novel kinase inhibitor with multiple targets. Nicotinamide promotes pancreatic cell differentiation from human embryonic stem cells (hESCs). However, its molecular mechanism is still unclear. In order to understand the molecular mechanism involved in pancreatic cell fate determination, we analyzed the downstream pathways of nicotinamide in the derivation of NKX6.1+ pancreatic progenitors from hESCs. METHODS: We applied downstream modulators of nicotinamide during the induction from posterior foregut to pancreatic progenitors, including niacin, PARP inhibitor, SIRT inhibitor, CK1 inhibitor and ROCK inhibitor. The impact of those treatments was evaluated by quantitative real-time PCR, flow cytometry and immunostaining of pancreatic markers. Furthermore, CK1 isoforms were knocked down to validate CK1 function in the induction of pancreatic progenitors. Finally, RNA-seq was used to demonstrate pancreatic induction on the transcriptomic level. RESULTS: First, we demonstrated that nicotinamide promoted pancreatic progenitor differentiation in chemically defined conditions, but it did not act through either niacin-associated metabolism or the inhibition of PARP and SIRT pathways. In contrast, nicotinamide modulated differentiation through CK1 and ROCK inhibition. We demonstrated that CK1 inhibitors promoted the generation of PDX1/NKX6.1 double-positive pancreatic progenitor cells. shRNA knockdown revealed that the inhibition of CK1α and CK1ε promoted pancreatic progenitor differentiation. We then showed that nicotinamide also improved pancreatic progenitor differentiation through ROCK inhibition. Finally, RNA-seq data showed that CK1 and ROCK inhibition led to pancreatic gene expression, similar to nicotinamide treatment. CONCLUSIONS: In this report, we revealed that nicotinamide promotes generation of pancreatic progenitors from hESCs through CK1 and ROCK inhibition. Furthermore, we discovered the novel role of CK1 in pancreatic cell fate determination.


Assuntos
Células-Tronco Embrionárias Humanas , Diferenciação Celular , Endoderma , Humanos , Niacinamida/farmacologia , Pâncreas
12.
Expert Opin Investig Drugs ; 30(8): 803-811, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34130563

RESUMO

Introduction: Tyrosine kinase inhibitors (TKIs) have drastically changed the outcome of chronic myeloid leukemia (CML) patients. However, a subset of patients experienced resistance and/or intolerance and need to switch to other agents. Resistance to second-generation TKIs used in first-line treatment is less of an issue when compared to imatinib in first line. New drugs that are able to improve efficacy, without long-term off-target effects are needed. Allosteric inhibitors such as asciminib (ABL001) were created to overcome resistance and off-target toxicity.Areas covered: In this review, we report the mechanism of action, pharmacokinetic data, and the clinical trial results of asciminib tested in chronic phase CML patients.Expert Opinion: Asciminib, the first example of allosteric inhibition, could be a promising approach as third-line therapy and in the subset of patients with T315I mutation that, for coexistent comorbidities, cannot receive other drugs. Future results will probably help to move the drug to earlier lines of treatment.


Assuntos
Antineoplásicos/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Niacinamida/análogos & derivados , Pirazóis/farmacologia , Regulação Alostérica/efeitos dos fármacos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Niacinamida/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos
14.
Nat Commun ; 12(1): 2665, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976125

RESUMO

With age, hematopoietic stem cells (HSC) undergo changes in function, including reduced regenerative potential and loss of quiescence, which is accompanied by a significant expansion of the stem cell pool that can lead to haematological disorders. Elevated metabolic activity has been implicated in driving the HSC ageing phenotype. Here we show that nicotinamide riboside (NR), a form of vitamin B3, restores youthful metabolic capacity by modifying mitochondrial function in multiple ways including reduced expression of nuclear encoded metabolic pathway genes, damping of mitochondrial stress and a decrease in mitochondrial mass and network-size. Metabolic restoration is dependent on continuous NR supplementation and accompanied by a shift of the aged transcriptome towards the young HSC state, more youthful bone marrow cellular composition and an improved regenerative capacity in a transplant setting. Consequently, NR administration could support healthy ageing by re-establishing a more youthful hematopoietic system.


Assuntos
Envelhecimento , Células-Tronco Hematopoéticas/efeitos dos fármacos , NAD/metabolismo , Niacinamida/análogos & derivados , Compostos de Piridínio/farmacologia , Fatores Etários , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células Cultivadas , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Biológicos , Niacinamida/farmacologia , Fosforilação Oxidativa/efeitos dos fármacos
15.
Acta Chim Slov ; 68(1): 65-71, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34057532

RESUMO

Two newly synthesized nicotinohydrazones, 6-bromo-2'-(2-chlorobenzylidene)nicotinohydrazide (1) and 6-bromo-2'-(3-bromo-5-chloro-2-hydroxybenzylidene)nicotinohydrazide methanol solvate (2), have been obtained and structurally characterized by spectroscopic method and single crystal X-ray determination. The molecules in both compounds are in E configuration regarding to the azomethine groups. The molecules of compound 1 are linked via hydrogen bonds of N?H∙∙∙O, generating one dimensional chains running along the c-axis direction. The hydrazone molecules of compound 2 are linked by methanol molecules via hydrogen bonds of N?H∙∙∙O and O?H∙∙∙N, generating dimers. The in vitro antimicrobial activities of these compounds indicate that they are interesting antibacterial agents.


Assuntos
Antibacterianos/farmacologia , Hidrazonas/farmacologia , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Antibacterianos/síntese química , Bactérias/efeitos dos fármacos , Cristalografia por Raios X , Hidrazonas/síntese química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Niacinamida/síntese química
16.
Lab Invest ; 101(9): 1225-1237, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33846538

RESUMO

Macrophages play an essential role in alcohol-induced inflammation and oxidative stress. We investigated the effects of nicotinamide riboside (NR), a natural nicotinamide adenine dinucleotide (NAD+) precursor, on alcohol-induced inflammation and oxidative stress in macrophages. NR significantly decreased ethanol-induced inflammatory gene expression, with a concomitant decrease in nuclear translocation of nuclear factor κB p65 in RAW 264.7 macrophages and mouse bone marrow-derived macrophages (BMDMs). In macrophages incubated with ethanol or acetaldehyde, NR abolished the accumulation of cellular reactive oxygen species. Ethanol decreased sirtuin 1 (SIRT1) expression and activity, and cellular NAD+ level while inducing pro-inflammatory gene expression. However, NR markedly attenuated the changes. SIRT1 inhibition augmented ethanol-induced inflammatory gene expression, but its activation elicited opposing effects. Also, ethanol did not alter glycolysis but increased glycolytic capacity, glycolytic reserve, and non-glycolytic acidification, with concomitant increases in hypoxia-induced factor 1α expression and activity, phosphorylation of pyruvate dehydrogenase, and extracellular lactate levels. Interestingly, ethanol increased mitochondrial respiration and ATP production but decreased maximal respiration and spare respiration capacity. The latter was linked to decreases in mitochondrial copy numbers. NR abolished the ethanol-induced metabolic changes in the glycolytic and oxidative phosphorylation pathways in RAW 264.7 macrophages. In conclusion, NR exerts anti-inflammatory and antioxidant properties by abrogating the inhibitory effects of ethanol on the SIRT1 pathway by increasing Sirt1 expression and its activator, NAD+. Also, SIRT1 activation and normalization of ethanol-induced changes in NAD+/NADH ratios by NR are likely crucial to counteract the changes in energy phenotypes of macrophages exposed to ethanol.


Assuntos
Inflamação/metabolismo , Macrófagos , Niacinamida/análogos & derivados , Estresse Oxidativo/efeitos dos fármacos , Compostos de Piridínio/farmacologia , Sirtuína 1/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Etanol/efeitos adversos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Niacinamida/farmacologia , Células RAW 264.7
17.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804001

RESUMO

Pyridine nucleotides such as a nicotinamide adenine dinucleotide (NAD) are known as plant defense activators. We previously reported that nicotinamide mononucleotide (NMN) enhanced disease resistance against fungal pathogen Fusarium graminearum in barley and Arabidopsis. In this study, we reveal that the pretreatment of nicotinamide (NIM), which does not contain nucleotides, effectively suppresses disease development of Fusarium Head Blight (FHB) in wheat plants. Correspondingly, deoxynivalenol (DON) mycotoxin accumulation was also significantly decreased by NIM pretreatment. A metabolome analysis showed that several antioxidant and antifungal compounds such as trigonelline were significantly accumulated in the NIM-pretreated spikes after inoculation of F. graminearum. In addition, some metabolites involved in the DNA hypomethylation were accumulated in the NIM-pretreated spikes. On the other hand, fungal metabolites DON and ergosterol peroxide were significantly reduced by the NIM pretreatment. Since NIM is relative stable and inexpensive compared with NMN and NAD, it may be more useful for the control of symptoms of FHB and DON accumulation in wheat and other crops.


Assuntos
Fusarium/efeitos dos fármacos , Niacinamida/farmacologia , Doenças das Plantas/prevenção & controle , Triticum/microbiologia , Fusarium/metabolismo , Fusarium/patogenicidade , Doenças das Plantas/microbiologia , Tricotecenos/metabolismo , Triticum/efeitos dos fármacos
18.
Food Chem ; 356: 129696, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-33838605

RESUMO

This study aimed to assess the effects of acetylation levels on actomyosin disassociation and phosphorylation of lamb during incubation at 4 °C. Samples of whole proteins from lamb longissimus thoracis muscles were prepared and assigned into three treatments (high, middle and low acetylation groups). The results showed that deacetylation of myosin heavy chain and actin was inhibited by lysine deacetylase inhibitor trichostatin A and nicotinamide in this study. Phosphorylation levels of myosin heavy chain and actin were inhibited by their acetylation during incubation in vitro. Actomyosin disassociation degree in high acetylation group was significantly lower than that in middle and low acetylation groups (P < 0.05). The ATPase activity in high acetylation group was significantly higher than that in middle and low acetylation groups (P < 0.05). In conclusion, acetylation of myosin heavy chain and actin inhibited actomyosin dissociation by inhibiting their phosphorylation at 4 °C in vitro.


Assuntos
Actomiosina/metabolismo , Músculos/metabolismo , Acetilação/efeitos dos fármacos , Actinas/antagonistas & inibidores , Actinas/metabolismo , Actomiosina/antagonistas & inibidores , Animais , Sítios de Ligação , Temperatura Baixa , Ácidos Hidroxâmicos/farmacologia , Simulação de Dinâmica Molecular , Cadeias Pesadas de Miosina/antagonistas & inibidores , Cadeias Pesadas de Miosina/metabolismo , Niacinamida/farmacologia , Fosforilação , Ovinos
19.
Biomolecules ; 11(2)2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33670751

RESUMO

SIRT1 is the most extensively studied human sirtuin with a broad spectrum of endogenous targets. It has been implicated in the regulation of a myriad of cellular events, such as gene transcription, mitochondria biogenesis, insulin secretion as well as glucose and lipid metabolism. From a mechanistic perspective, nicotinamide (NAM), a byproduct of a sirtuin-catalyzed reaction, reverses a reaction intermediate to regenerate NAD+ through "base exchange", leading to the inhibition of the forward deacetylation. NAM has been suggested as a universal sirtuin negative regulator. Sirtuins have evolved different strategies in response to NAM regulation. Here, we report the detailed kinetic analysis of SIRT1-catalyzed reactions using endogenous substrate-based synthetic peptides. A novel substrate-dependent sensitivity of SIRT1 to NAM inhibition was observed. Additionally, SIRT1 demonstrated pH-dependent deacetylation with normal solvent isotope effects (SIEs), consistent with proton transfer in the rate-limiting step. Base exchange, in contrast, was insensitive to pH changes with no apparent SIEs, indicative of lack of proton transfer in the rate-limiting step. Consequently, NAM inhibition was attenuated at a high pH in proteated buffers. Our study provides new evidence for "activation by de-repression" as an effective sirtuin activation strategy.


Assuntos
Niacinamida/farmacologia , Sirtuína 1/metabolismo , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/genética , Epigenômica , Humanos , Concentração de Íons de Hidrogênio , Sirtuína 1/genética
20.
Toxicol Appl Pharmacol ; 418: 115492, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33722665

RESUMO

Cisplatin is a commonly used anti-cancer drug, but it induces nephrotoxicity. As a water-soluble vitamin B family member, nicotinamide (NAM) was recently demonstrated to have beneficial effects for renal injury, but its underlying mechanism remains largely unclear. Here, we suggest that NAM may exert protective effects against cisplatin-induced acute kidney injury (AKI) mainly via suppressing the poly ADP-ribose polymerase 1 (PARP1)/p53 pathway. In our experiment, NAM protected against cisplatin-induced apoptosis both in cultured renal proximal tubular cells and AKI in mice. Mechanistically, NAM suppressed the expression and activation of p53, a known mediator of cisplatin-induced AKI. Upstream of p53, NAM attenuated the induction of γ-H2AX, a hallmark of DNA damage response. Interestingly, PARP1 was activated in cisplatin AKI and this activation was inhibited by NAM. Pharmacological inhibition of PARP1 with PJ34 significantly ameliorated p53 activation and cisplatin-induced cell death in RPTCs and AKI in mice. Thus, NAM may protect against cisplatin-induced AKI by suppressing the PARP1/p53 pathway.


Assuntos
Injúria Renal Aguda/prevenção & controle , Cisplatino , Túbulos Renais Proximais/efeitos dos fármacos , Niacinamida/farmacologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/enzimologia , Injúria Renal Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Histonas/metabolismo , Túbulos Renais Proximais/enzimologia , Túbulos Renais Proximais/patologia , Masculino , Camundongos Endogâmicos C57BL , Fosfoproteínas/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Ratos , Transdução de Sinais
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