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1.
Biol Pharm Bull ; 46(2): 147-157, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36724942

RESUMO

Intron recognition by the spliceosome mainly depends on conserved intronic sequences such as 5' splice sites, 3' splice sites, and branch sites. Therefore, even substitution of just a single nucleotide in a 5' or 3' splice site abolishes the splicing at the mutated site and leads to cryptic splice site usage. A number of disease-causative mutations have been found in 5' and 3' splice sites, but the genes with these mutations still maintain the correct protein-coding sequence, so recovery of splicing at the mutated splice site may produce a normal protein. Mutations in the spliceosome components have been shown to change the balance between the conformational transition and disassembly of the spliceosome, which affects the decision about whether the reaction of the incorporated substrate will proceed. In addition, the lower disassembly rate caused by such mutations induces splicing of the mutated splice site. We hypothesized that small compounds targeting the spliceosome may include a compound mimicking the effect of those mutations. Thus, we screened a small-compound library and identified a compound, BAY61-3606, that changed the cellular small nuclear ribonucleoprotein composition and also showed activity of enhancing splicing at the mutated 3' splice site of the reporter gene, as well as splicing at the suboptimal 3' splice site of endogenous cassette exons. These results indicate that further analysis of the mechanism of action of BAY61-3606 could enable modulation of the fidelity of splicing.


Assuntos
Sítios de Splice de RNA , Spliceossomos , Sítios de Splice de RNA/genética , Spliceossomos/genética , Spliceossomos/metabolismo , Ribonucleoproteínas Nucleares Pequenas/genética , Ribonucleoproteínas Nucleares Pequenas/metabolismo , Niacinamida , Mutação
2.
Nutrients ; 15(2)2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36678315

RESUMO

Disrupted biological function, manifesting through the hallmarks of aging, poses one of the largest threats to healthspan and risk of disease development, such as metabolic disorders, cardiovascular ailments, and neurodegeneration. In recent years, numerous geroprotectors, senolytics, and other nutraceuticals have emerged as potential disruptors of aging and may be viable interventions in the immediate state of human longevity science. In this review, we focus on the decrease in nicotinamide adenine dinucleotide (NAD+) with age and the supplementation of NAD+ precursors, such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), in combination with other geroprotective compounds, to restore NAD+ levels present in youth. Furthermore, these geroprotectors may enhance the efficacy of NMN supplementation while concurrently providing their own numerous health benefits. By analyzing the prevention of NAD+ degradation through the inhibition of CD38 or supporting protective downstream agents of SIRT1, we provide a potential framework of the CD38/NAD+/SIRT1 axis through which geroprotectors may enhance the efficacy of NAD+ precursor supplementation and reduce the risk of age-related diseases, thereby potentiating healthspan in humans.


Assuntos
NAD , Sirtuína 1 , Humanos , Adolescente , NAD/metabolismo , Senoterapia , Niacinamida/farmacologia , Niacinamida/metabolismo , Mononucleotídeo de Nicotinamida , Nucleotídeos , Suplementos Nutricionais
3.
Acta Neuropathol Commun ; 11(1): 18, 2023 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-36681854

RESUMO

Glaucoma is the leading cause of irreversible blindness and is a major health and economic burden. Current treatments do not address the neurodegenerative component of glaucoma. In animal models of glaucoma, the capacity to maintain retinal nicotinamide adenine dinucleotide (NAD) pools declines early during disease pathogenesis. Treatment with nicotinamide, an NAD precursor through the NAD salvage pathway, robustly protects against neurodegeneration in a number of glaucoma models and improves vision in existing glaucoma patients. However, it remains unknown in humans what retinal cell types are able to process nicotinamide to NAD and how these are affected in glaucoma. To address this, we utilized publicly available RNA-sequencing data (bulk, single cell, and single nucleus) and antibody labelling in highly preserved enucleated human eyes to identify expression of NAD synthesizing enzyme machinery. This identifies that the neural retina favors expression of the NAD salvage pathway, and that retinal ganglion cells are particularly enriched for these enzymes. NMNAT2, a key terminal enzyme in the salvage pathway, is predominantly expressed in retinal ganglion cell relevant layers of the retina and declines in glaucoma. These findings suggest that human retinal ganglion cells can directly utilize nicotinamide and could maintain a capacity to do so in glaucoma, showing promise for ongoing clinical trials.


Assuntos
Glaucoma , NAD , Animais , Humanos , NAD/metabolismo , Niacinamida/metabolismo , Retina/patologia , Glaucoma/patologia , Nervo Óptico/patologia , Células Ganglionares da Retina/patologia
4.
Toxins (Basel) ; 15(1)2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36668859

RESUMO

BACKGROUND: Panton-Valentine Leukocidin sustains a strong cytotoxic activity, targeting immune cells and, consequently, perforating the plasma membrane and inducing cell death. The present study is aimed to examine the individual effect of ascorbic acid and nicotinamide on PVL cytotoxicity ex vivo, as well as their effect on granulocytes viability when treated with PVL. MATERIALS AND METHODS: The PVL cytotoxicity assay was performed in triplicates using the commercial Cytotoxicity Detection Kit PLUS (LDH). LDH release was measured to determine cell damage and cell viability was measured via flow cytometry. RESULTS AND DISCUSSION: A clear reduction in PVL cytotoxicity was demonstrated (p < 0.001). Treatment with ascorbic acid at 5 mg/mL has shown a 3-fold reduction in PVL cytotoxicity; likewise, nicotinamide illustrated a 4-fold reduction in PVL cytotoxicity. Moreover, granulocytes' viability after PVL treatment was maintained when incubated with 5 mg/mL of ascorbic acid and nicotinamide. CONCLUSIONS: our findings illustrated that ascorbic acid and nicotinamide exhibit an inhibitory effect on PVL cytotoxicity and promote cell viability, as the cytotoxic effect of the toxin is postulated to be neutralized by antioxidant incubation. Further investigations are needed to assess whether these antioxidants may be viable options in PVL cytotoxicity attenuation in PVL-associated diseases.


Assuntos
Toxinas Bacterianas , Infecções Estafilocócicas , Humanos , Ácido Ascórbico/farmacologia , Niacinamida/farmacologia , Toxinas Bacterianas/toxicidade , Exotoxinas/toxicidade , Leucocidinas/toxicidade
5.
Int J Mol Sci ; 24(2)2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36675198

RESUMO

Sorafenib is currently a targeted agent widely used in the treatment of advanced hepatocellular carcinoma (aHCC). However, to date there is still a lack of a reliable marker capable of predicting sorafenib therapeutic responses. Here, we conducted a genome-wide association study (GWAS) to identify candidate single-nucleotide polymorphism outcome predictors in aHCC patients. A total of 74 real-world sorafenib-treated aHCC patients were enrolled for GWAS and outcome analysis. GWAS showed that rs1010816 (p = 2.2 × 10-7) was associated with sorafenib therapeutic response in aHCC patients. Kaplan-Meier analysis indicated that the "TT" genotype was significantly associated with a favorable therapeutic response but not significantly associated with overall survival (OS). Univariate followed by multivariate Cox proportional hazard analysis showed that ascites, main portal vein thrombosis, lower platelet count, lower total sorafenib doses, higher PALBI score in model A and higher ALBI grade in model B were significantly associated with a shorter OS. Subgroup analysis showed that only in alcoholic aHCC patients treated by sorafenib, rs1010816 "TT" genotype was significantly associated with longer OS (p = 0.021). Sorafenib had a favorable therapeutic outcome in alcoholic aHCC patients carrying rs1010816 "TT" genotype.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Sorafenibe/uso terapêutico , Polimorfismo de Nucleotídeo Único , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Estudo de Associação Genômica Ampla , Antineoplásicos/uso terapêutico , Resultado do Tratamento , Estudos Retrospectivos , Compostos de Fenilureia/uso terapêutico , Niacinamida/uso terapêutico
6.
J Med Chem ; 66(2): 1301-1320, 2023 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-36598465

RESUMO

We report [1,2,4]triazolo[3,4-b]benzothiazole (TBT) as a new inhibitor scaffold, which competes with nicotinamide in the binding pocket of human poly- and mono-ADP-ribosylating enzymes. The binding mode was studied through analogues and cocrystal structures with TNKS2, PARP2, PARP14, and PARP15. Based on the substitution pattern, we were able to identify 3-amino derivatives 21 (OUL243) and 27 (OUL232) as inhibitors of mono-ARTs PARP7, PARP10, PARP11, PARP12, PARP14, and PARP15 at nM potencies, with 27 being the most potent PARP10 inhibitor described to date (IC50 of 7.8 nM) and the first PARP12 inhibitor ever reported. On the contrary, hydroxy derivative 16 (OUL245) inhibits poly-ARTs with a selectivity toward PARP2. The scaffold does not possess inherent cell toxicity, and the inhibitors can enter cells and engage with the target protein. This, together with favorable ADME properties, demonstrates the potential of TBT scaffold for future drug development efforts toward selective inhibitors against specific enzymes.


Assuntos
Inibidores de Poli(ADP-Ribose) Polimerases , Tanquirases , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/química , Niacinamida/farmacologia , Desenvolvimento de Medicamentos , Benzotiazóis/farmacologia , Poli(ADP-Ribose) Polimerases , Proteínas Proto-Oncogênicas/metabolismo
7.
Eur J Med Chem ; 248: 115080, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36608458

RESUMO

Nicotinamide phosphoribosyl transferase (NAMPT) has been regarded as an attractive target for cancer therapy. However, there is a lack of chemical tools for real-time visualization and detection of NAMPT. Herein, the first fluorescent and theranostic probes were designed for imaging NAMPT, which had dual functions of diagnosis and treatment. The designed probes possessed good affinity and environmental sensitivity to NAMPT with a turn-on mechanism and were successfully applied in fluorescence detecting and imaging of NAMPT at the level of living cells and tissue sections. They also effectively inhibited tumor cell proliferation and arrested cell cycle at the G2 phase. These fluorescent probes enabled detection and visualization of NAMPT, representing effective chemical tools for the pathological diagnosis and treatment of cancer.


Assuntos
Neoplasias , Medicina de Precisão , Humanos , Citocinas/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Proliferação de Células , Niacinamida
8.
Eur J Pharmacol ; 941: 175490, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36608862

RESUMO

We investigated and compared the pharmacologic properties of two Janus kinase (JAK) inhibitors, peficitinib and tofacitinib, in an adjuvant-induced arthritis rat model. Repeated administration of peficitinib (3 - 30 mg/kg) or tofacitinib (1 - 10 mg/kg) exhibited a dose-related and significant attenuation of arthritis score, paw swelling, pain threshold, grip strength and histopathologic injuries in the model; peficitinib 10 mg/kg and tofacitinib 3 mg/kg demonstrated comparable efficacy. Equivalent Cmax and AUC0-12h values were observed with peficitinib 10 mg/kg and tofacitinib 3 mg/kg, suggesting that the two drugs may demonstrate comparable efficacy on arthritis-associated symptoms at comparable plasma concentration levels. However, peficitinib 10 mg/kg had greater efficacy than tofacitinib 3 mg/kg on some inflammation- and bone destruction-associated parameters in the paw fluid, including the production of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), receptor activator of nuclear factor kappa-B ligand, and matrix metalloproteinase-3, which are associated with arthritis exacerbation. Peficitinib 10 mg/kg also showed significantly greater inhibitory effects than tofacitinib 3 mg/kg on loss of bone mineral density and synovial thickening score, which might be a result of the VEGF and PDGF receptor kinase inhibitory effects of peficitinib, in addition to JAK inhibition. In conclusion, both tofacitinib and peficitinib potently improved arthritis and associated symptoms in adjuvant-induced arthritis rats; moreover, owing to possible differences in the mechanism of action of the two drugs, peficitinib may have exerted its effects through JAK inhibition and additional unique off-target properties.


Assuntos
Artrite Experimental , Inibidores de Janus Quinases , Ratos , Animais , Fator A de Crescimento do Endotélio Vascular , Niacinamida/farmacologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico
9.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 54(1): 14-19, 2023 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-36647637

RESUMO

Nicotinamide (NAM) is the amide form of niacin and one of the precursors of nicotinamide adenine dinucleotide (NAD +). NAM can be used as a dietary supplement or clinical therapeutic drug to replenish NAD + levels in the human body and participate in key bodily functions such as cellular metabolism and DNA repair. NAM has the advantage of low cost, wide availability, and sound biosafety. It also has multiple biological functions, including antibacterial effect, anti-inflammatory effect, and modulation of cellular immunity, producing significant ameliorative effects on skin and neurodegenerative diseases. However, most studies on NAM are still at the laboratory stage. Herein we reviewed the role and mechanism of NAM in the prevention and treatment of oral and systemic diseases, explored its potential as clinical therapeutic medication, provided some basis and references for the clinical application of nicotinamide in the prevention and treatment of various diseases, and discussed its prospects for future research and application.


Assuntos
NAD , Niacinamida , Humanos , Niacinamida/farmacologia , Niacinamida/uso terapêutico , NAD/metabolismo , Pele/metabolismo , Boca/metabolismo , Face
10.
Pharm Biol ; 61(1): 189-200, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36625086

RESUMO

CONTEXT: Lysiphyllum strychnifolium (Craib) A. Schmitz (LS) (Fabaceae) has traditionally been used to treat diabetes mellitus. OBJECTIVE: This study demonstrates the antidiabetic and antioxidant effects of aqueous extract of LS leaves in vivo and in vitro. MATERIALS AND METHODS: The effects of aqueous LS leaf extract on glucose uptake, sodium-dependent glucose cotransporter 1 (SGLT1) and glucose transporter 2 (GLUT2) mRNA expression in Caco-2 cells, α-glucosidase, and lipid peroxidation were evaluated in vitro. The antidiabetic effects were evaluated using an oral glucose tolerance test (OGTT) and a 28-day consecutive administration to streptozotocin (STZ)-nicotinamide (NA)-induced type 2 diabetic mice. RESULTS: The extract significantly inhibited glucose uptake (IC50: 236.2 ± 36.05 µg/mL) and downregulated SGLT1 and GLUT2 mRNA expression by approximately 90% in Caco-2 cells. Furthermore, it non-competitively inhibited α-glucosidase in a concentration-dependent manner with the IC50 and Ki of 6.52 ± 0.42 and 1.32 µg/mL, respectively. The extract at 1000 mg/kg significantly reduced fasting blood glucose levels in both the OGTT and 28-day consecutive administration models as compared with untreated STZ-NA-induced diabetic mice (p < 0.05). Significant improvements of serum insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and GLUT4 levels were observed. Furthermore, the extract markedly decreased oxidative stress markers by 37-53% reduction of superoxide dismutase 1 (SOD1) in muscle and malondialdehyde (MDA) in muscle and pancreas, which correlated with the reduction of MDA production in vitro (IC50: 24.80 ± 7.24 µg/mL). CONCLUSION: The LS extract has potent antihyperglycemic activity to be used as alternative medicine to treat diabetes mellitus.


Assuntos
Diabetes Mellitus Experimental , alfa-Glucosidases , Humanos , Camundongos , Animais , alfa-Glucosidases/metabolismo , Glicemia , Células CACO-2 , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Niacinamida , RNA Mensageiro , Estreptozocina
11.
Magn Reson Med ; 89(2): 565-576, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36300851

RESUMO

PURPOSE: The average saturation efficiency filter (ASEF) is a novel method of improving the specificity of CEST; however, there is a mismatch between the magnetization transfer (MT) effect under high-duty cycle and low-duty cycle pulse trains. We explore measures of mitigation and the sensitivity and potential of ASEF imaging in phantoms and stroke rats. METHODS: Simulation and nicotinamide phantoms in denatured protein were used to investigate the effect of different average saturation powers and MT pool parameters on matching coefficients used for correction as well as the ASEF ratio signal and baseline. Then, in vivo studies were performed in stroke rodents to further investigate the sensitivity and fidelity of ASEF ratio spectra. RESULTS: Simulation and studies of nicotinamide phantoms show that the matching coefficient needed to correct the baseline MT mismatch is strongly dependent on the average saturation power. In vivo studies in stroke rodents show that the matching coefficient required to correct the baseline MT mismatch is different for normal versus ischemic tissue. Thus, a baseline correction was performed to further suppress the residue MT mismatch. After correction of the mismatch, ASEF ratio achieved comparable contrast at 3.6 ppm between normal and ischemic tissue when compared to the apparent amide proton transfer (APT*) approach. Moreover, contrasts for 2.0 and 2.6 ppm were also ascertainable from the same spectra. CONCLUSION: ASEF can improve the CEST signal specificity of slow exchange labile protons such as amide and guanidyl, with small loss to sensitivity. It has strong potential in the CEST imaging of various diseases.


Assuntos
Roedores , Acidente Vascular Cerebral , Animais , Ratos , Roedores/metabolismo , Imageamento por Ressonância Magnética/métodos , Acidente Vascular Cerebral/diagnóstico por imagem , Prótons , Amidas/química , Niacinamida
12.
Drugs Aging ; 40(1): 33-48, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36510042

RESUMO

The role of nicotinamide adenine dinucleotide (NAD+) in ageing has emerged as a critical factor in understanding links to a wide range of chronic diseases. Depletion of NAD+, a central redox cofactor and substrate of numerous metabolic enzymes, has been detected in many major age-related diseases. However, the mechanisms behind age-associated NAD+ decline remains poorly understood. Despite limited conclusive evidence, supplements aimed at increasing NAD+ levels are becoming increasingly popular. This review provides renewed insights regarding the clinical utility and benefits of NAD+ precursors, namely nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), in attenuating NAD+ decline and phenotypic characterization of age-related disorders, including metabolic, cardiovascular and neurodegenerative diseases. While it is anticipated that NAD+ precursors can play beneficial protective roles in several conditions, they vary in their ability to promote NAD+ anabolism with differing adverse effects. Careful evaluation of the role of NAD+, whether friend or foe in ageing, should be considered.


Assuntos
NAD , Doenças Neurodegenerativas , Humanos , NAD/metabolismo , Niacinamida/metabolismo , Mononucleotídeo de Nicotinamida/metabolismo , Suplementos Nutricionais , Envelhecimento/metabolismo
13.
Aging Cell ; 22(1): e13754, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36515353

RESUMO

Declining nicotinamide adenine dinucleotide (NAD+ ) concentration in the brain during aging contributes to metabolic and cellular dysfunction and is implicated in the pathogenesis of aging-associated neurological disorders. Experimental therapies aimed at boosting brain NAD+ levels normalize several neurodegenerative phenotypes in animal models, motivating their clinical translation. Dietary intake of NAD+ precursors, such as nicotinamide riboside (NR), is a safe and effective avenue for augmenting NAD+ levels in peripheral tissues in humans, yet evidence supporting their ability to raise NAD+ levels in the brain or engage neurodegenerative disease pathways is lacking. Here, we studied biomarkers in plasma extracellular vesicles enriched for neuronal origin (NEVs) from 22 healthy older adults who participated in a randomized, placebo-controlled crossover trial (NCT02921659) of oral NR supplementation (500 mg, 2x /day, 6 weeks). We demonstrate that oral NR supplementation increases NAD+ levels in NEVs and decreases NEV levels of Aß42, pJNK, and pERK1/2 (kinases involved in insulin resistance and neuroinflammatory pathways). In addition, changes in NAD(H) correlated with changes in canonical insulin-Akt signaling proteins and changes in pERK1/2 and pJNK. These findings support the ability of orally administered NR to augment neuronal NAD+ levels and modify biomarkers related to neurodegenerative pathology in humans. Furthermore, NEVs offer a new blood-based window into monitoring the physiologic response of NR in the brain.


Assuntos
Vesículas Extracelulares , Doenças Neurodegenerativas , Idoso , Humanos , Biomarcadores , Vesículas Extracelulares/metabolismo , Insulina , NAD/metabolismo , Niacinamida/farmacologia , Niacinamida/metabolismo
14.
Chem Biol Interact ; 370: 110305, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36529159

RESUMO

Ribavirin is a common antiviral drug, especially for patients with hepatitis C. Our recent studies demonstrated that ribavirin showed anti-tumor activity in colorectal cancer and hepatocellular carcinoma, but its effects on lung cancer remains unclear. This study aimed to evaluate the anti-tumor activity of ribavirin against lung cancer and elucidate the underlying mechanism. We established orthotopic mouse model of lung cancer (LLC and GLC-82) and employed an ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS)-based metabolomics approach. We found that ribavirin significantly inhibited the proliferation and colony formation of lung cancer cells. Tumor sizes of orthotopic lung cancer in ribavirin-treated groups were also significantly lower than those in control groups. Metabolomics analysis revealed that ribavirin mainly affected 5 metabolic pathways in orthotopic lung tumor models, taurine and hypotaurine metabolism, nicotinate and nicotinamide metabolism, linoleic acid metabolism, arginine biosynthesis and arachidonic acid metabolism. Furthermore, we identified 5 upregulated metabolites including ß-nicotinamide adenine dinucleotide (NAD+), nicotinamide (NAM), taurine, ornithine and citrulline, and 7 downregulated metabolites including 1-methylnicotinamide (MNAM), S-adenosyl-l-homocysteine (SAH), N1-Methyl-2-pyridone-5-carboxamide (2PY), homocysteine (Hcy), linoleic acid, arachidonic acid (AA) and argininosuccinic acid in ribavirin-treated groups. These results provide new insight into the anti-tumor mechanism of ribavirin for lung cancer.


Assuntos
Neoplasias Pulmonares , Ribavirina , Camundongos , Animais , Ribavirina/farmacologia , Ribavirina/uso terapêutico , Ácido Araquidônico , Ácido Linoleico , Metabolômica/métodos , Neoplasias Pulmonares/tratamento farmacológico , Cromatografia Líquida de Alta Pressão/métodos , Niacinamida , Taurina , Biomarcadores
15.
Chem Biol Interact ; 370: 110329, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36565974

RESUMO

Until recently, sorafenib has been the only treatment approved by the U.S. Food and Drug Administration for patients with advanced hepatocellular carcinoma (HCC). Some patients, however, exhibit resistance to this treatment and subsequently experience cancer progression, recurrence, or death. Therefore, identifying a new alternative treatment for patients with little or no response to sorafenib treatment is vital. In this study, we explored the therapeutic potential and underlying molecular mechanism of antrocinol ((3aS,4R,6aS,10aR)-4-(hydroxymethyl)-7,7-dimethyldecahydro-1H-naphtho[1,8a-c]furan-1-one) in patients with HCC. The results indicated that antrocinol was more therapeutically effective than antrocin, Stivarga, and sorafenib against HCC cell lines. Antrocinol also substantially suppressed the expression of KRAS-GTP, p-MEK1/2, p-ERK1/2, and p-AKT in the Huh7 cell line. Additionally, antrocinol-induced apoptosis in the Huh7 cell line, inhibited the formation of tumorspheres, and suppressed the expression of cancer stem cell markers CD133, KLF4, CD44, OCT4, SOX2, and c-Myc. Animal studies revealed that antrocinol alone considerably suppressed tumor growth in nonobese diabetic/severe combined immunodeficient mice inoculated with Huh7 tumorspheres. It also synergistically enhanced the anticancer effect of sorafenib, resulting in enhanced suppression of tumor growth (p < 0.001) and tumorsphere formation (p < 0.001). In tumor samples resected from mice treated with antrocinol alone or in combination with sorafenib, immunohistochemical analysis revealed an increase in BAX expression and a decrease in ERK and AKT protein expression. To the best of our knowledge, this is the first report of the anti-HCC activity of antrocinol. With its higher therapeutic efficacy than that of sorafenib, antrocinol is a candidate drug for patients with HCC who demonstrate little or no response to sorafenib treatment.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Carcinoma Hepatocelular/patologia , Proteínas Proto-Oncogênicas p21(ras) , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular Tumoral , Transdução de Sinais , Niacinamida/farmacologia , Apoptose
16.
Sci Rep ; 12(1): 20886, 2022 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-36463304

RESUMO

REM sleep without atonia (RSWA) is a key feature for the diagnosis of rapid eye movement (REM) sleep behaviour disorder (RBD). We introduce RBDtector, a novel open-source software to score RSWA according to established SINBAR visual scoring criteria. We assessed muscle activity of the mentalis, flexor digitorum superficialis (FDS), and anterior tibialis (AT) muscles. RSWA was scored manually as tonic, phasic, and any activity by human scorers as well as using RBDtector in 20 subjects. Subsequently, 174 subjects (72 without RBD and 102 with RBD) were analysed with RBDtector to show the algorithm's applicability. We additionally compared RBDtector estimates to a previously published dataset. RBDtector showed robust conformity with human scorings. The highest congruency was achieved for phasic and any activity of the FDS. Combining mentalis any and FDS any, RBDtector identified RBD subjects with 100% specificity and 96% sensitivity applying a cut-off of 20.6%. Comparable performance was obtained without manual artefact removal. RBD subjects also showed muscle bouts of higher amplitude and longer duration. RBDtector provides estimates of tonic, phasic, and any activity comparable to human scorings. RBDtector, which is freely available, can help identify RBD subjects and provides reliable RSWA metrics.


Assuntos
Transtorno do Comportamento do Sono REM , Sono REM , Humanos , Hipotonia Muscular , Transtorno do Comportamento do Sono REM/diagnóstico , Software , Músculos Faciais , Cafeína , Niacinamida
17.
JASA Express Lett ; 2(11): 114402, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36456371

RESUMO

When the ear is stimulated by two tones presented at frequencies f1 and f2, nonlinearity in the cochlea's vibratory response leads to the generation of distortion products (DPs), with the cubic 2f1-f2 DP commonly viewed as the most prominent. While the quadratic f2-f1 DP is also evident in numerous physiological and perceptual studies, its presence in the cochlea's mechanical response has been less well documented. Here, examination of vibratory DPs within the mouse cochlea confirmed that f2-f1 was a significant and sometimes dominant component, whether DPs were measured near their generation site, or after having propagated from more basal locations.


Assuntos
Cóclea , Vibração , Camundongos , Animais , Cafeína , Niacinamida
18.
Cell Metab ; 34(12): 1947-1959.e5, 2022 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-36476934

RESUMO

Nicotinamide adenine dinucleotide (NAD) is an essential redox cofactor in mammals and microbes. Here we use isotope tracing to investigate the precursors supporting NAD synthesis in the gut microbiome of mice. We find that dietary NAD precursors are absorbed in the proximal part of the gastrointestinal tract and not available to microbes in the distal gut. Instead, circulating host nicotinamide enters the gut lumen and supports microbial NAD synthesis. The microbiome converts host-derived nicotinamide into nicotinic acid, which is used for NAD synthesis in host tissues and maintains circulating nicotinic acid levels even in the absence of dietary consumption. Moreover, the main route from oral nicotinamide riboside, a widely used nutraceutical, to host NAD is via conversion into nicotinic acid by the gut microbiome. Thus, we establish the capacity for circulating host micronutrients to feed the gut microbiome, and in turn be transformed in a manner that enhances host metabolic flexibility.


Assuntos
NAD , Niacina , Camundongos , Animais , Niacinamida/farmacologia , Mamíferos
19.
Cell Host Microbe ; 30(12): 1649-1650, 2022 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-36521437

RESUMO

Recently in Cell Metabolism, Challapa et al. used isotope labeling to track NAD metabolism in host tissues and the gut microbiota. They describe a symbiotic relationship in which the gut microbiota uses host-derived nicotinamide to generate NAD and in return, produces nicotinic acid for host NAD biosynthesis.


Assuntos
NAD , Niacina , NAD/metabolismo , Niacinamida/metabolismo , Niacina/metabolismo
20.
Int J Mol Sci ; 23(24)2022 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-36555845

RESUMO

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The AKT pathway is often activated in HCC cases, and a longer exposure to tyrosine kinase inhibitors such as sorafenib may lead to over-activation of the AKT pathway, leading to HCC resistance. Here, we studied the efficacy of a new generation of allosteric AKT inhibitor, vevorisertib, alone or in combination with sorafenib. To identify specific adverse effects related to the background of cirrhosis, we used a diethylnitrosamine (DEN)-induced cirrhotic rat model. Vevorisertib was tested in vitro on Hep3B, HepG2, HuH7 and PLC/PRF cell lines. Rats were treated weekly with intra-peritoneal injections of DEN for 14 weeks to obtain cirrhosis with fully developed HCC. After that, rats were randomized into four groups (n = 7/group): control, sorafenib, vevorisertib and the combination of vevorisertib + sorafenib, and treated for 6 weeks. Tumor progression was followed by MRI. We demonstrated that the vevorisertib is a highly potent treatment, blocking the phosphorylation of AKT. The tumor progression in the rat liver was significantly reduced by treatment with vevorisertib + sorafenib (49.4%) compared to the control group (158.8%, p < 0.0001). Tumor size, tumor number and tumor cell proliferation were significantly reduced in both the vevorisertib group and vevorisertib + sorafenib groups compared to the control group. Sirius red staining showed an improvement in liver fibrosis by vevorisertib and the combination treatment. Moreover, vevorisertib + sorafenib treatment was associated with a normalization in the liver vasculature. Altogether, vevorisertib as a single agent and its combination with sorafenib exerted a strong suppression of tumor progression and improved liver fibrosis. Thus, results provide a rationale for testing vevorisertib in clinical settings and confirm the importance of targeting AKT in HCC.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Ratos , Animais , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Carcinoma Hepatocelular/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Hepáticas/metabolismo , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proliferação de Células , Cirrose Hepática/tratamento farmacológico
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