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1.
Ther Adv Respir Dis ; 16: 17534666221137277, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36404753

RESUMO

OBJECTIVE: Radiation-induced lung injury (RILI) is one of the serious complications of radiotherapy. We have recently demonstrated that nicaraven can effectively mitigate RILI in healthy mice. Here, we further tried to optimize the dose and time of nicaraven administration for alleviating the side effects of radiotherapy in tumor-bearing mice. METHODS AND RESULTS: A subcutaneous tumor model was established in the back of the chest in C57BL/6N mice by injecting Lewis lung cancer cells. Therapeutic thoracic irradiations were done, and placebo or different doses of nicaraven (20, 50, 100 mg/kg) were administrated intraperitoneally pre-irradiation (at almost 5-10 min before irradiation) or post-irradiation (within 5 min after irradiation). Mice that received radiotherapy and nicaraven were sacrificed on the 30th day, but control mice were sacrificed on the 15th day. Serum and lung tissues were collected for evaluation. Nicaraven significantly decreased the level of CCL8, but did not clearly change the levels of 8-OHdG, TGF-ß, IL-1ß, and IL-6 in serum. Besides these, nicaraven effectively decreased the levels of TGF-ß, IL-1ß, and SOD2 in the lungs, especially by post-irradiation administration with the dose of 20 mg/kg. Although there was no significant difference, the expression of SOD1, 53BP1, and caspase 3 was detected lower in the lungs of mice received nicaraven post-irradiation than that of pre-irradiation. CONCLUSION: According to our data, the administration of nicaraven at a relatively low dose soon after radiotherapy will be recommended for attenuating the side effects of radiotherapy.


Assuntos
Neoplasias , Niacinamida , Camundongos , Humanos , Animais , Camundongos Endogâmicos C57BL , Niacinamida/farmacologia , Fator de Crescimento Transformador beta
2.
Int J Mol Sci ; 23(21)2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36361882

RESUMO

Doxorubicin, which is widely used to treat a broad spectrum of malignancies, has pronounced dose-dependent side effects leading to chronic heart failure development. Nicotinamide riboside (NR) is one of the promising candidates for leveling the cardiotoxic effect. In the present work, we performed a comparative study of the cardioprotective and therapeutic actions of various intravenous NR administration modes in chronic doxorubicin-induced cardiomyopathy in Wistar rats. The study used 60 mature male SPF Wistar rats. The animals were randomized into four groups (a control group and three experimental groups) which determined the doxorubicin (intraperitoneally) and NR (intravenous) doses as well as the specific modes of NR administration (combined, preventive). We demonstrated the protective effect of NR on the cardiovascular system both with combined and preventive intravenous drug administration, which was reflected in a fibrous tissue formation decrease, reduced fractional-shortening decrease, and better antioxidant system performance. At the same time, it is important to note that the preventive administration of NR had a more significant protective effect on the animal organism as a whole. This was confirmed by better physical activity parameters and vascular bed conditions. Thus, the data obtained during the study can be used for further investigation into chronic doxorubicin-induced cardiomyopathy prevention and treatment approaches.


Assuntos
Cardiomiopatias , Niacinamida , Ratos , Animais , Masculino , Ratos Wistar , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Compostos de Piridínio/farmacologia , Compostos de Piridínio/uso terapêutico , Doxorrubicina/efeitos adversos , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/prevenção & controle , NAD
3.
J Popul Ther Clin Pharmacol ; 29(3): e17-e33, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36196935

RESUMO

PURPOSE: To investigate the protective role of SRT1720 (SIRT1 activator) against the oxidative stress caused by H2O2 in the corneal cell line. METHODS: Human corneal (2.040 pRSV-T) cell lines were cultured and treated with SRT1720 (as SIRT1 activator) and nicotinamide (NAM, a SIRT1 inhibitor), and incubated with H2O2. The expression level of SIRT1, p53, and acetyl-p53 was measured by western blot. Propidium iodine/annexin V-FITC staining, and flow cytometry was used to evaluate apoptosis. The trypan blue assay was used to assess the morphological modifications that occurred after the treatment, and Pifithrin-α (PFT-α) was used to inhibit the p53 pathway. RESULTS: The investigation revealed that under oxidative stress, SRT1720 caused a reduction in acetyl-p53 expression and increased SIRT1 expression. It was also found that under oxidative stress, SRT1720 suppressed apoptosis. In comparison, NAM promoted cell apoptosis under oxidative stress. NAM's destructive effect was eliminated by PFT-α, a suppressor of the p53 pathway. PFT-α reduced the morphological changes in 2.040 pRSV-T cell lines compared to NAM treatment and inhibited apoptosis. CONCLUSIONS: The protective effects of the SIRT1 activator (SRT1720) indicate that H2O2 induces oxidative stress-associated cell damage. The results also encouraged us to consider using SRT1720 to improve corneal safety and reduce the adverse effects of oxidative damage.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis , Sirtuína 1 , Benzotiazóis , Células Epiteliais/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Peróxido de Hidrogênio/toxicidade , Niacinamida/farmacologia , Sirtuína 1/metabolismo , Tolueno/análogos & derivados , Proteína Supressora de Tumor p53/metabolismo
4.
Int J Mol Sci ; 23(20)2022 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-36293365

RESUMO

The Scandinavian region is home to a unique biome with endemic plant species. The aim of this study was to explore this natural diversity and identify plant extracts providing positive skin barrier effects. Six plant extracts were identified as starting material. Following biochemical screening, two candidates outperformed the rest: Betula alba (BA) and Empetrum nigrum (EN). Quantitative PCR analysis showed that BA and EN upregulated barrier genes, when used individually and in combination. Betula alba increased AQP3 and OCLN protein expression, something niacinamide was incapable of. Additionally, the skin barrier was strengthened, evidenced by inhibition of KLK5 and hyaluronidase and showed strong antioxidant and anti-inflammatory activity through DPPH and COX2 inhibition, respectively. A first split-face clinical study was conducted using the combination of extracts versus placebo. There was a significantly better skin restructuring effect and corneocyte cohesion on the side treated with combined extracts. A second split-face clinical study assessed the combined extracts versus 3% niacinamide. Significant variations in skin hydration and TEWL were observed in favor of the extract treated side. In conclusion, we identified a natural alternative to niacinamide for improving skin barrier health, in Scandinavian plant extracts, which yield strong performance, but at a lower concentration.


Assuntos
Ericaceae , Casca de Planta , Antioxidantes , Betula , Ciclo-Oxigenase 2/genética , Sucos de Frutas e Vegetais , Hialuronoglucosaminidase , Niacinamida/farmacologia , Extratos Vegetais/farmacologia
5.
J Med Chem ; 65(21): 14642-14654, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36288465

RESUMO

NNMT uses SAM as a cofactor to catalyze the methylation of nicotinamide, producing 1-methylnicotinamide. Recent studies have shown that NNMT upregulation in cancer-associated fibroblasts (CAFs) is required to maintain the CAF phenotype in high-grade serous carcinoma. These observations suggest that NNMT should be evaluated as a therapeutic target, especially in cancer. Although several small-molecule inhibitors of NNMT have been identified, there remains a need for highly potent and selective inhibitors with excellent in vivo activity and ADME properties that can be used as reliable chemical probes. We have identified azaindoline carboxamide 38 as a selective and potent NNMT inhibitor with favorable PK/PD and safety profiles as well as excellent oral bioavailability and pharmaceutical properties. Our mechanistic studies indicate that 38 binds uncompetitively with SAM but competitively with nicotinamide consistent with its binding in the nicotinamide binding site and likely forming a positive interaction with SAM.


Assuntos
Niacinamida , Nicotinamida N-Metiltransferase , Niacinamida/farmacologia , Niacinamida/metabolismo , Sítios de Ligação , Metilação
6.
Bioorg Chem ; 129: 106174, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36191428

RESUMO

A series of novel nitric oxide (NO)-releasing 5,8-quinolinedione/furoxan hybrids (8a-h and 9a-h) were designed and synthesized through coupling different alkanolamine substituted phenylsulfonyl furoxan with 5,8-quinolinedione. Most compounds displayed high cytotoxic activity against drug-sensitive/-resistant cancer cells. In particular, the IC50 of 9a (0.42 µM) was about 9-fold lower than that of ß-lap (3.69 µM) and 12-fold lower than that of SAHA (5.24 µM) in drug-resistant cancer cells. Also, 9a was demonstrated to selectively inhibit the growth of Bel7402/5-FU cancer cells. Mechanistic studies demonstrated that 9a could serve as an NO donor and nicotinamide quinone oxidoreductase 1 (NQO1) inhibitor (IC50 = 0.8 µM), which could induce the highest level of NO and reactive oxygen species (ROS) in Bel-7402/5-FU cancer cells. Furthermore, 9a could promote tumor cell apoptosis and autophagy via regulation of apoptosis-related protein (Bax, Bcl-2, and Caspase 3) and autophagy-associated proteins (LC3 and p62) in Bel-7402/5-FU cells. Taken together, 9a may be considered as a promising candidate for a further comprehensive study involving drug-resistant hepatocellular carcinoma.


Assuntos
Antineoplásicos , Neoplasias Hepáticas , Humanos , Óxido Nítrico/metabolismo , Niacinamida/farmacologia , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/metabolismo , Apoptose , Neoplasias Hepáticas/tratamento farmacológico , Fluoruracila/farmacologia , Proliferação de Células , NAD(P)H Desidrogenase (Quinona)
7.
J Neuroinflammation ; 19(1): 232, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36131290

RESUMO

BACKGROUND: Early life stress (ELS) is associated with the development of schizophrenia later in life. The hippocampus develops significantly during childhood and is extremely reactive to stress. In rodent models, ELS can induce neuroinflammation, hippocampal neuronal loss, and schizophrenia-like behavior. While nicotinamide (NAM) can inhibit microglial inflammation, it is unknown whether NAM treatment during adolescence reduces hippocampal neuronal loss and abnormal behaviors induced by ELS. METHODS: Twenty-four hours of maternal separation (MS) of Wistar rat pups on post-natal day (PND)9 was used as an ELS. On PND35, animals received a single intraperitoneal injection of BrdU to label dividing neurons and were given NAM from PND35 to PND65. Behavioral testing was performed. Western blotting and immunofluorescence staining were used to detect nicotinamide adenine dinucleotide (NAD+)/Sirtuin3 (Sirt3)/superoxide dismutase 2 (SOD2) pathway-related proteins. RESULTS: Compared with controls, only MS animals in the adult stage (PND56-65) but not the adolescent stage (PND31-40) exhibited pre-pulse inhibition deficits and cognitive impairments mimicking schizophrenia symptoms. MS decreased the survival and activity of puberty-born neurons and hippocampal NAD+ and Sirt3 expression in adulthood. These observations were related to an increase in acetylated SOD2, microglial activation, and significant increases in pro-inflammatory IL-1ß, TNF-α, and IL-6 expression. All the effects of MS at PND9 were reversed by administering NAM in adolescence (PND35-65). CONCLUSIONS: MS may lead to schizophrenia-like phenotypes and persistent hippocampal abnormalities. NAM may be a safe and effective treatment in adolescence to restore normal hippocampal function and prevent or ameliorate schizophrenia-like behavior.


Assuntos
Privação Materna , Sirtuína 3 , Animais , Bromodesoxiuridina/metabolismo , Cognição , Hipocampo/metabolismo , Interleucina-6/metabolismo , NAD/metabolismo , NAD/farmacologia , Neurônios/metabolismo , Niacinamida/metabolismo , Niacinamida/farmacologia , Ratos , Ratos Wistar , Maturidade Sexual , Fator de Necrose Tumoral alfa/metabolismo
8.
Virulence ; 13(1): 1533-1542, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36068709

RESUMO

Amphotericin B (AmB) is a widely used antifungal agent especially for the therapy of systemic fungal infections. However, the severe side effects of AmB often leads to the premature termination of the treatment. So it is imperative to find the drugs that can both reduce the dosage and enhance the antifungal efficacy of AmB. Here we demonstrated that Nicotinamide (NAM), a cheap and safe vitamin, could enhance the antifungal activities of AmB. We demonstrated the synergistic interaction of NAM and AmB against Candida albicans as well as other Candida spp. and Cryptococcus neoformans. Moreover, NAM could enhance of the activity of AmB against biofilm. This enhancement was also observed in disseminated candidiasis in vivo. Our further study revealed that AmB could induce oxidative damage through the modification of histone acetylation. AmB could inhibit the expression of HST3, an H3K56 deacetylase in C. albicans. The immunoblotting test revealed excessive H3K56ac in AmB-treated fungal cells. Consistantly, the hst3Δ mutant displayed high sensitivity to AmB, while addition of NAM, an H3K56 deacetylation inhibitor, resulted in an even severe inhibition in the growth of this strain. These results indicated that AmB could execute antifungal activity via boosting H3K56ac which was mediated by HST3, and the mechanism for the synergistic interaction of NAM and AmB was based on exacerbating this process, which led to even excessive H3K56ac and oxidative damage. This finding provided theoretical basis for better understanding the antifungal mechanisms of AmB and clinical application of this drug.


Assuntos
Anfotericina B , Candidíase , Anfotericina B/farmacologia , Antifúngicos/uso terapêutico , Candida albicans/genética , Candidíase/tratamento farmacológico , Humanos , Testes de Sensibilidade Microbiana , Niacinamida/farmacologia , Niacinamida/uso terapêutico
9.
Artigo em Chinês | MEDLINE | ID: mdl-36052583

RESUMO

Objective: To investigate the protective effect and mechanism of Nicotinamide Riboside (NR) on lung injury caused by Paraquat intoxicated mice. Methods: Eighty clean male BALB/C mice were selected and averagely divided forty mice into 4 groups with 10 mice in each group, PQ group was given 25% PQ solution (60 mg/kg) by one-time gavage. PQ+NR group were intraperitoneally injected with NR solution (300 mg/kg) 1 hour before given the same amount of PQ solution (60 mg/kg) by one-time gavage, The Control group were given the same amount of saline by one-time gavage, The same amount of NR was intraperitoneally injected before NR group were given saline by one-time gavage. Observed and recorded general condition of PQ intoxicated mice. Observed and recorded the death of mice every half an hour and counted the mortality and drew survival curve of each group after 72 hours exposure. another forty mice were averagely divided and treated by the same way. After 24 hours of modelling, mice were anaesthetized and killed. Then blood was extracted after eyeball was removed. The changes of TNF-a、IL-6 and MPO in serum of mice were detected by ELISA.Two lung tissues were removed from the chest and used to measure the D/W ratio of the lung. The pathological changes of lung were observed and scored under light microscope.The levels of SOD, MDA and Caspase-3 in lung tissues were determined by chemical colorimetry. The expression of Sirt1 and Nrf2 in lung tissues was detected by Western-blot. Results: Compared with the Control group and the NR group, the mice in the PQ group had a poor general condition, such as depression, crouching, skin disorder and reduced activity, food, urine and feces. The symptoms in the PQ+NR group were reduced compared with the PQ group. The survival rate at 72 hours after exposure: 80% in the PQ+NR group and 40% higher than that in the PQ group (P=0.029) . Compared with Control group and NR group, the D/W ratio (0.09±0.07) , lung pathology score under light microscope (11.80±0.37) , TNF-a (39.89±1.48) pg/ml、IL-6 (77.29±2.38) pg/ml、MPO (0.31±0.01) µg/ml、SOD (6.62±0.30) U/mgprot、MDA level (1.21±0.14) mmol/mgprot, Caspase-3 activity (356.00± 27.16) %, Sirt1 and Nrf2 protein expression (1.02±0.14、0.82±0.06) were significantly decreased in PQ group (P=0.004、0.023) ; Compared with PQ group, PQ+NR group significantly increased the D/W ratio (0.10±0.10) , decreased the pulmonary pathology score under light microscope (7.400.51) , decreased TNF-a (33.00± 0.65) pg/ml、IL-6 (52.23±4.23) pg/ml、MPO leve (0.23±0.01) µg/mll, increased SOD leve (9.28±0.45) U/mgprotl, decreased MDA level (0.78±0.02) mmol/mgprot, decreased Caspase-3 activity (222.80±7.59) %, and increased the protein expressions of Sirt1 and Nrf2 (1.62±0.16、1.06±0.04) (P=0.048、0.035) . Conclusion: NR can prolong the survival time of PQ poisoned mice; NR intervention can effectively inhibit the inflammatory response, peroxidation injury and apoptosis of PQ poisoned mice; NR intervention can upregulate the expression of Sirt1 and Nrf2 protein and effectively reduce the lung injury of PQ poisoning.


Assuntos
Lesão Pulmonar , Niacinamida , Paraquat , Compostos de Piridínio , Animais , Caspase 3/metabolismo , Interleucina-6/metabolismo , Pulmão , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/metabolismo , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Paraquat/toxicidade , Compostos de Piridínio/farmacologia , Sirtuína 1/metabolismo , Superóxido Dismutase/metabolismo
10.
Int J Biol Macromol ; 221: 1415-1427, 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36096255

RESUMO

To overcome the low bioavailability of lipophilic free thymoquinone (TQ), this study aims to evaluate a novel oral formula of TQ-loaded chitosan nanoparticles (TQ-CsNPs) for the effective treatment of diabetes. The XRD, FTIR, FESEM, HRTEM, and dynamic light scattering were all conducted on the prepared formula. The release pattern of TQ, cytotoxicity against MRC-5 cell line (human lung fibroblast cells), and antidiabetic activity on streptozotocin/nicotinamide (STZ/NA) rat model of diabetes were investigated. The results confirmed the formation of TQ-CsNPs with an entrapment efficiency of 75.7 ± 6.52 %, a mean Zetasizer distribution of 84.25 nm, and an average particle size of about 50 nm. After 24 h, the percentage of free TQ-cumulative release was approximately 35.8 %, whereas TQ-CsNPs showed a sustained release pattern of 78.5 %. The investigated formula was not toxic to normal lung cells, and more efficient in ameliorating the altered glycemia, dyslipidemia, inflammation, and oxidative stress induced by STZ/NA than free TQ, blank CsNPs, and metformin-HCl (as a reference drug). Additionally, TQ-CsNPs restored the normal pancreatic islets' configuration and morphometry, suggesting a potent insulinotropic action. In conclusion, the antidiabetic efficacy of TQ was improved by engaging TQ with CsNPs as an excellent nanoplatform to enhance the oral bioavailability of TQ.


Assuntos
Quitosana , Diabetes Mellitus Experimental , Nanopartículas , Animais , Ratos , Humanos , Estreptozocina , Niacinamida/farmacologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Benzoquinonas/farmacologia , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico
11.
Sci Rep ; 12(1): 15440, 2022 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-36104373

RESUMO

Nicotinamide N-methyltransferase (NNMT) is a metabolic regulator that catalyzes the methylation of nicotinamide (Nam) using the co-factor S-adenosyl-L-methionine to form 1-methyl-nicotinamide (MNA). Overexpression of NNMT and the presence of the active metabolite MNA is associated with a number of diseases including metabolic disorders. We conducted a high-throughput screening campaign that led to the identification of a tricyclic core as a potential NNMT small molecule inhibitor series. Elaborate medicinal chemistry efforts were undertaken and hundreds of analogs were synthesized to understand the structure activity relationship and structure property relationship of this tricyclic series. A lead molecule, JBSNF-000028, was identified that inhibits human and mouse NNMT activity, reduces MNA levels in mouse plasma, liver and adipose tissue, and drives insulin sensitization, glucose modulation and body weight reduction in a diet-induced obese mouse model of diabetes. The co-crystal structure showed that JBSNF-000028 binds below a hairpin structural motif at the nicotinamide pocket and stacks between Tyr-204 (from Hairpin) and Leu-164 (from central domain). JBSNF-000028 was inactive against a broad panel of targets related to metabolism and safety. Interestingly, the improvement in glucose tolerance upon treatment with JBSNF-000028 was also observed in NNMT knockout mice with diet-induced obesity, pointing towards the glucose-normalizing effect that may go beyond NNMT inhibition. JBSNF-000028 can be a potential therapeutic option for metabolic disorders and developmental studies are warranted.


Assuntos
Doenças Metabólicas , Nicotinamida N-Metiltransferase , Animais , Glucose , Humanos , Doenças Metabólicas/tratamento farmacológico , Camundongos , Niacinamida/metabolismo , Niacinamida/farmacologia , Nicotinamida N-Metiltransferase/metabolismo , Nitrosaminas , Obesidade/tratamento farmacológico , Tiramina/análogos & derivados
12.
Int J Biochem Cell Biol ; 151: 106292, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36038127

RESUMO

This study aimed to investigate the putative role of nicotinamide N-methyltransferase in the metabolic response of human aortic endothelial cells. This enzyme catalyses S-adenosylmethionine-mediated methylation of nicotinamide to methylnicotinamide. This reaction is accompanied by the reduction of the intracellular nicotinamide and S-adenosylmethionine content. This may affect NAD+ synthesis and various processes of methylation, including epigenetic modifications of chromatin. Particularly high activity of nicotinamide N-methyltransferase is detected in liver, many neoplasms as well as in various cells in stressful conditions. The elevated nicotinamide N-methyltransferase content was also found in endothelial cells treated with statins. Although the exogenous methylnicotinamide has been postulated to induce a vasodilatory response, the specific metabolic role of nicotinamide N-methyltransferase in vascular endothelium is still unclear. Treatment of endothelial cells with bacterial lipopolysaccharide evokes several metabolic and functional consequences which built a multifaceted physiological response of endothelium to bacterial infection. Among the spectrum of biochemical changes substantially elevated protein level of nicotinamide N-methyltransferase was particularly intriguing. Here it has been shown that silencing of the nicotinamide N-methyltransferase gene influences several changes which are observed in cells treated with lipopolysaccharide. They include altered energy metabolism and rearrangement of the mitochondrial network. A complete explanation of the mechanisms behind the protective consequences of the nicotinamide N-methyltransferase deficiency in cells treated with lipopolysaccharide needs further investigation.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Nicotinamida N-Metiltransferase , Cromatina/metabolismo , Células Endoteliais/metabolismo , Endotélio/metabolismo , Metabolismo Energético , Humanos , Lipopolissacarídeos/farmacologia , NAD/metabolismo , Niacinamida/metabolismo , Niacinamida/farmacologia , Nicotinamida N-Metiltransferase/genética , Nicotinamida N-Metiltransferase/metabolismo , S-Adenosilmetionina/metabolismo
13.
Cardiovasc Toxicol ; 22(10-11): 898-909, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35986807

RESUMO

Hypertension caused by a high-salt (HS) diet is one of the major causes of cardiovascular diseases. Underlining pathology includes oxidative stress and inflammation in the hypothalamic paraventricular nucleus (PVN). This study investigates genistein's (Gen) role in HS-induced hypertension and the underlying molecular mechanism. We placed male Wistar rats on HS (8% NaCl) or normal salt diet (0.3% NaCl). Then, we injected bilateral PVN in rats with Gen, vehicle, or nicotinamide (NAM) for 4 weeks. Tail cuff was used weekly to assess the systolic pressure, diastolic pressure, and mean arterial pressure (MAP). Cardiac hypertrophy was analyzed by heart weight/body weight ratio and wheat germ agglutinin staining. ELISA kits, Western blot, or dihydroethidium staining determined the levels of inflammatory cytokines and oxidative stress markers. Western blot measured protein levels of Sirt1, Ac-FOXO1, Nrf2, NQO-1, HO-1, and gp91phox. Our result showed that PVN infusion of Gen significantly reduced the increase of systolic pressure, diastolic pressure, and MAP induced by an HS diet. Additionally, there was a decrease in cardiac hypertrophy and the levels of inflammatory cytokines in PVN and plasma. Meanwhile, PVN infusion of Gen notably inhibited the levels of oxidized glutathione and superoxide dismutase and improved the glutathione level and total antioxidant capacities and superoxide dismutase activities. It also decreased the level of reactive oxygen species and gp91phox expression in PVN. Furthermore, Gen infusion markedly increases the Sirt1, Nrf2, HO-1, and NQO-1 levels and decreases the Ac-FOXO1 level. However, PVN infusion of NAM could significantly block these changes induced by Gen in HS diet rats. Our results demonstrated that PVN infusion of Gen could inhibit the progression of hypertension induced by an HS diet by activating the Sirt1/Nrf2 pathway.


Assuntos
Genisteína , Hipertensão , Estresse Oxidativo , Núcleo Hipotalâmico Paraventricular , Animais , Masculino , Ratos , Antioxidantes/metabolismo , Cardiomegalia/patologia , Citocinas/metabolismo , Genisteína/farmacologia , Dissulfeto de Glutationa/metabolismo , Hipertensão/induzido quimicamente , Hipertensão/prevenção & controle , Hipertensão/metabolismo , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Fator 2 Relacionado a NF-E2/metabolismo , Niacinamida/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/metabolismo , Cloreto de Sódio na Dieta/efeitos adversos , Superóxido Dismutase/metabolismo
14.
Biomolecules ; 12(8)2022 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-36009002

RESUMO

Inhibition of Plasmodium falciparum nicotinamidase could represent a potential antimalarial since parasites require nicotinic acid to successfully recycle nicotinamide to NAD+, and importantly, humans lack this biosynthetic enzyme. Recently, mechanism-based inhibitors of nicotinamidase have been discovered. The most potent compound inhibits both recombinant P. falciparum nicotinamidase and parasites replication in infected human red blood cells (RBCs). These studies provide evidence for the importance of nicotinamide salvage through nicotinamidase as a central master player of NAD+ homeostasis in P. falciparum.


Assuntos
Antimaláricos , Niacina , Antimaláricos/farmacologia , Humanos , NAD , Niacinamida/farmacologia , Nicotinamidase , Plasmodium falciparum
15.
Mol Metab ; 64: 101560, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35940554

RESUMO

OBJECTIVE: Mitochondrial disorders are often characterized by muscle weakness and fatigue. Null mutations in the heart-muscle adenine nucleotide translocator isoform 1 (ANT1) of both humans and mice cause cardiomyopathy and myopathy associated with exercise intolerance and muscle weakness. Here we decipher the molecular underpinnings of ANT1-deficiency-mediated exercise intolerance. METHODS: This was achieved by correlating exercise physiology, mitochondrial function and metabolomics of mice deficient in ANT1 and comparing this to control mice. RESULTS: We demonstrate a peripheral limitation of skeletal muscle mitochondrial respiration and a reduced complex I respiration in ANT1-deficient mice. Upon exercise, this results in a lack of NAD+ leading to a substrate limitation and stalling of the TCA cycle and mitochondrial respiration, further limiting skeletal muscle mitochondrial respiration. Treatment of ANT1-deficient mice with nicotinamide riboside increased NAD+ levels in skeletal muscle and liver, which increased the exercise capacity and the mitochondrial respiration. CONCLUSION: Increasing NAD+ levels with nicotinamide riboside can alleviate the exercise intolerance associated to ANT1-deficiency, indicating the therapeutic potential of NAD+-stimulating compounds in mitochondrial myopathies.


Assuntos
Translocador 1 do Nucleotídeo Adenina , Miopatias Mitocondriais , NAD , Niacinamida , Condicionamento Físico Animal , Compostos de Piridínio , Translocador 1 do Nucleotídeo Adenina/genética , Animais , Camundongos , Miopatias Mitocondriais/genética , Debilidade Muscular , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Isoformas de Proteínas , Compostos de Piridínio/farmacologia
16.
Cell Mol Life Sci ; 79(8): 463, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35918544

RESUMO

Alterations in cellular nicotinamide adenine dinucleotide (NAD+) levels have been observed in multiple lifestyle and age-related medical conditions. This has led to the hypothesis that dietary supplementation with NAD+ precursors, or vitamin B3s, could exert health benefits. Among the different molecules that can act as NAD+ precursors, Nicotinamide Riboside (NR) has gained most attention due to its success in alleviating and treating disease conditions at the pre-clinical level. However, the clinical outcomes for NR supplementation strategies have not yet met the expectations generated in mouse models. In this review we aim to provide a comprehensive view on NAD+ biology, what causes NAD+ deficits and the journey of NR from its discovery to its clinical development. We also discuss what are the current limitations in NR-based therapies and potential ways to overcome them. Overall, this review will not only provide tools to understand NAD+ biology and assess its changes in disease situations, but also to decide which NAD+ precursor could have the best therapeutic potential.


Assuntos
NAD , Niacinamida , Animais , Modelos Animais de Doenças , Camundongos , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Compostos de Piridínio/uso terapêutico
17.
Molecules ; 27(15)2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35956878

RESUMO

Nicotinamide nucleotide transhydrogenase (NNT) is involved in decreasing melanogenesis through tyrosinase degradation induced by cellular redox changes. Nicotinamide is a component of coenzymes, such as NAD+, NADH, NADP+, and NADPH, and its levels are modulated by NNT. Vitamin C and polydeoxyribonucleotide (PDRN) are also known to decrease skin pigmentation. We evaluated whether a mixture of nicotinamide, vitamin C, and PDRN (NVP-mix) decreased melanogenesis by modulating mitochondrial oxidative stress and NNT expression in UV-B-irradiated animals and in an in vitro model of melanocytes treated with conditioned media (CM) from UV-B-irradiated keratinocytes. The expression of NNT, GSH/GSSG, and NADPH/NADP+ in UV-B-irradiated animal skin was significantly decreased by UV-B radiation but increased by NVP-mix treatment. The expression of NNT, GSH/GSSG, and NADPH/NADP+ ratios decreased in melanocytes after CM treatment, although they increased after NVP-mix administration. In NNT-silenced melanocytes, the GSH/GSSG and NADPH/NADP+ ratios were further decreased by CM compared with normal melanocytes. NVP-mix decreased melanogenesis signals, such as MC1R, MITF, TYRP1, and TYRP2, and decreased melanosome transfer-related signals, such as RAB32 and RAB27A, in UV-B-irradiated animal skin. NVP-mix also decreased MC1R, MITF, TYRP1, TYRP2, RAB32, and RAB27A in melanocytes treated with CM from UV-irradiated keratinocytes. The expression of MC1R and MITF in melanocytes after CM treatment was unchanged by NNT silencing. However, the expression of TYRP1, TYRP2, RAB32, and RAB27A increased in NNT-silenced melanocytes after CM treatment. NVP-mix also decreased tyrosinase activity and melanin content in UV-B-irradiated animal skin and CM-treated melanocytes. In conclusion, NVP-mix decreased mitochondrial oxidative stress by increasing NNT expression and decreased melanogenesis by decreasing MC1R/MITF, tyrosinase, TYRP1, and TYRP2.


Assuntos
NADP Trans-Hidrogenases , Animais , Ácido Ascórbico/metabolismo , Ácido Ascórbico/farmacologia , Dissulfeto de Glutationa/metabolismo , Melaninas , Melanócitos/metabolismo , Monofenol Mono-Oxigenase/metabolismo , NADP/metabolismo , NADP Trans-Hidrogenases/metabolismo , Niacinamida/metabolismo , Niacinamida/farmacologia , Polidesoxirribonucleotídeos/metabolismo , Vitaminas/metabolismo
18.
J Enzyme Inhib Med Chem ; 37(1): 2206-2222, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35980113

RESUMO

New nicotinamide derivatives 6, 7, 10, and 11 were designed and synthesised based on the essential features of the VEGFR-2 inhibitors. Compound 10 revealed the highest anti-proliferative activities with IC50 values of 15.4 and 9.8 µM against HCT-116 and HepG2, respectively compared to sorafenib (IC50 = 9.30 and 7.40 µM). Compound 7 owned promising cytotoxic activities with IC50 values of 15.7 and 15.5 µM against the same cell lines, respectively. Subsequently, the VEGFR-2 inhibitory activities were assessed for the titled compounds to exhibit VEGFR-2 inhibition with sub-micromolar IC50 values. Moreover, compound 7 induced the cell cycle cessation at the cycle at %G2-M and G0-G1phases, and induced apoptosis in the HCT-116. Compounds 7 and 10 reduced the levels of TNF-α by 81.6 and 84.5% as well as IL-6 by 88.4 and 60.9%, respectively, compared to dexamethasone (82.4 and 93.1%). In silico docking, molecular dynamics simulations, ADMET, and toxicity studies were carried out.


Assuntos
Antineoplásicos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Simulação de Acoplamento Molecular , Estrutura Molecular , Niacinamida/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade
19.
Eur J Pharmacol ; 931: 175186, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35977595

RESUMO

Tumor chemoresistance is often a major cause for the failure of chemotherapy. The resistance of hepatocellular carcinoma (HCC) cells to sorafenib significantly limits its therapeutic effect in HCC patients. For the first time, we found that FXYD domain-containing ion transport regulator 5 (FXYD5) is highly expressed in sorafenib-resistant HCC cells. In addition, the protein expression level of FXYD5 was markedly higher in HCC tissues than in paracancerous tissues. Remarkably, downregulation of FXYD5 expression in Huh7/sora cells reversed their resistance to sorafenib. Moreover, overexpression of FXYD5 reduced the sensitivity of HCC cells to sorafenib, while the downregulation of its expression in HCC cells had the opposite effect. We also found abnormal activation of the Akt/mTOR signaling pathway in Huh7/sora cells. Furthermore, MK2206, an Akt inhibitor, was found to significantly increase the sensitivity of HCC cells to sorafenib. More importantly, the expression level of p-Akt was positively correlated with the expression of FXYD5 in HCC tissues. Therefore, mechanistically, FXYD5 enhances the resistance of HCC cells to sorafenib by activating the Akt/mTOR signaling pathway. In conclusion, this study showed that the activation of the FXYD5/Akt/mTOR signaling axis plays key role in the resistance of HCC cells to sorafenib, and FXYD5 may represent a new potential target for HCC therapy.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Canais Iônicos/metabolismo , Neoplasias Hepáticas/patologia , Proteínas dos Microfilamentos/metabolismo , Niacinamida/farmacologia , Compostos de Fenilureia/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Sorafenibe/farmacologia , Serina-Treonina Quinases TOR/metabolismo
20.
J Oral Pathol Med ; 51(9): 801-809, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35996988

RESUMO

BACKGROUND: Radiation damage to salivary gland is inevitable in head and neck cancer patients receiving radiotherapy. Safe and effective treatments for protecting salivary glands from radiation are still unavailable. Mitochondrial damage is a critical mechanism in irradiated salivary gland; however, treatment targeting mitochondria has not received much attention. Nicotinamide is a key component of the mitochondrial metabolism. Here, we investigated the effects and underlying mechanisms of nicotinamide on protecting irradiated submandibular gland. METHODS: Submandibular gland cells and tissues were randomly divided into four groups: control, nicotinamide alone, radiation alone, and radiation with nicotinamide pretreatment. Cell viability was detected by PrestoBlue cell viability reagent. Histopathological alterations were observed with HE staining. Pilocarpine-stimulated saliva was measured from Wharton's duct. Cell apoptosis was determined by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Nicotinamide phosphoribosyl transferase was examined with immunofluorescence. The levels of nicotinamide adenine dinucleotide, mitochondrial membrane potential, and adenosine triphosphate were measured with the relevant kits. The mitochondrial ultrastructure was observed under transmission electron microscopy. RESULTS: Nicotinamide significantly mitigated radiation damage both in vitro and in vivo. Also, nicotinamide improved saliva secretion and reduced radiation-induced apoptosis in irradiated submandibular glands. Moreover, nicotinamide improved nicotinamide phosphoribosyl transferase and the levels of nicotinamide adenine dinucleotide/adenosine triphosphate and mitochondrial membrane potential, all of which were decreased by radiation in submandibular gland cells. Importantly, nicotinamide protected the mitochondrial ultrastructure from radiation. CONCLUSION: These findings demonstrate that nicotinamide alleviates radiation damage in submandibular gland by replenishing nicotinamide adenine dinucleotide and maintaining mitochondrial function and ultrastructure, suggesting that nicotinamide could be used as a prospective radioprotectant for preventing radiation sialadenitis.


Assuntos
Lesões por Radiação , Glândula Submandibular , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/farmacologia , Animais , DNA Nucleotidilexotransferase/metabolismo , DNA Nucleotidilexotransferase/farmacologia , Humanos , Mitocôndrias , NAD/metabolismo , NAD/farmacologia , Niacinamida/metabolismo , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Pilocarpina/farmacologia , Estudos Prospectivos , Lesões por Radiação/metabolismo , Lesões por Radiação/patologia , Ratos , Ratos Wistar , Glândula Submandibular/metabolismo
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