RESUMEN
BACKGROUND: Currently, treatment regimens for visceral leishmaniasis (VL) are limited because of the presence of numerous adverse effects. Nicotinamide, a readily available and cost-effective vitamin, has been widely acknowledged for its safety profile. Several studies have demonstrated the anti-leishmanial effects of nicotinamide in vitro. However, the potential role of nicotinamide in Leishmania infection in vivo remains elusive. METHODS: In this study, we assessed the efficacy of nicotinamide as a therapeutic intervention for VL caused by Leishmania infantum in an experimental mouse model and investigated its underlying molecular mechanisms. The potential molecular mechanism was explored through cytokine analysis, examination of spleen lymphocyte subsets, liver RNA-seq analysis, and pathway validation. RESULTS: Compared to the infection group, the group treated with nicotinamide demonstrated significant amelioration of hepatosplenomegaly and recovery from liver pathological damage. The NAM group exhibited parasite reduction rates of 79.7% in the liver and 86.7% in the spleen, respectively. Nicotinamide treatment significantly reduced the activation of excessive immune response in infected mice, thereby mitigating hepatosplenomegaly and injury. Furthermore, nicotinamide treatment enhanced fatty acid ß-oxidation by upregulating key enzymes to maintain lipid homeostasis. CONCLUSIONS: Our findings provide initial evidence supporting the safety and therapeutic efficacy of nicotinamide in the treatment of Leishmania infection in BALB/c mice, suggesting its potential as a viable drug for VL.
Asunto(s)
Leishmania infantum , Leishmaniasis Visceral , Metabolismo de los Lípidos , Hígado , Ratones Endogámicos BALB C , Niacinamida , Bazo , Animales , Leishmaniasis Visceral/tratamiento farmacológico , Leishmaniasis Visceral/parasitología , Leishmaniasis Visceral/inmunología , Niacinamida/farmacología , Niacinamida/uso terapéutico , Ratones , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/parasitología , Hígado/efectos de los fármacos , Hígado/patología , Leishmania infantum/efectos de los fármacos , Bazo/parasitología , Bazo/efectos de los fármacos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Inflamación/tratamiento farmacológico , Antiprotozoarios/farmacología , Antiprotozoarios/uso terapéuticoRESUMEN
AIM: We aimed to confirm the inhibitory effect of nicotinamide on fibrotic scar formation following spinal cord injury in mice using functional metabolomics. METHODS: We proposed a novel functional metabolomics strategy to establish correlations between gene expression changes and metabolic phenotypes using integrated multi-omics analysis. Through the integration of quantitative metabolites analysis and assessments of differential gene expression, we identified nicotinamide as a functional metabolite capable of inhibiting fibrotic scar formation and confirmed the effect in vivo using a mouse model of spinal cord injury. Furthermore, to mimic fibrosis models in vitro, primary mouse embryonic fibroblasts and spinal cord fibroblasts were stimulated by TGFß, and the influence of nicotinamide on TGFß-induced fibrosis-associated genes and its underlying mechanism were examined. RESULTS: Administration of nicotinamide led to a reduction in fibrotic lesion area and promoted functional rehabilitation following spinal cord injury. Nicotinamide effectively downregulated the expression of fibrosis genes, including Col1α1, Vimentin, Col4α1, Col1α2, Fn1, and Acta2, by repressing the TGFß/SMADs pathway. CONCLUSION: Our functional metabolomics strategy identified nicotinamide as a metabolite with the potential to inhibit fibrotic scar formation following SCI by suppressing the TGFß/SMADs signaling. This finding provides new therapeutic strategies and new ideas for clinical treatment.
Asunto(s)
Cicatriz , Fibrosis , Ratones Endogámicos C57BL , Niacinamida , Traumatismos de la Médula Espinal , Animales , Niacinamida/farmacología , Niacinamida/uso terapéutico , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/complicaciones , Cicatriz/tratamiento farmacológico , Cicatriz/patología , Cicatriz/metabolismo , Cicatriz/prevención & control , Ratones , Fibrosis/tratamiento farmacológico , Factor de Crecimiento Transformador beta/metabolismo , Metabolómica , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , FemeninoRESUMEN
Thioredoxin Reductase (TrxR) functions to recycle thioredoxin (Trx) during hydroperoxide metabolism mediated by peroxiredoxins and is currently being targeted using the FDA-approved anti-rheumatic drug, auranofin (AF), to selectively sensitize cancer cells to therapy. AF treatment decreased TrxR activity and clonogenic survival in small cell lung cancer (SCLC) cell lines (DMS273 and DMS53) as well as the H727 atypical lung carcinoid cell line. AF treatment also significantly sensitized DMS273 and H727 cell lines in vitro to sorafenib, an FDA-approved multi-kinase inhibitor that depleted intracellular glutathione (GSH). The pharmacokinetic, pharmacodynamic, and safety profile of AF was examined in nude mice with DMS273 xenografts administered AF intraperitoneally at 2 mg/kg or 4 mg/kg (IP) once (QD) or twice daily (BID) for 1-5 d. Plasma levels of AF were 10-20 µM (determined by mass spectrometry of gold), and the optimal inhibition of TrxR activity was obtained at 4 mg/kg once daily, with no effect on glutathione peroxidase 1 activity. This AF treatment extended for 14 d, inhibited TrxR (>75%), and resulted in a significant prolongation of median overall survival from 19 to 23 d (p = .04, N = 30 controls, 28 AF). In this experiment, there were no observed changes in animal bodyweight, complete blood counts (CBCs), bone marrow toxicity, blood urea nitrogen, or creatinine. These results support the hypothesis that AF effectively inhibits TrxR both in vitro and in vivo in SCLC, sensitizes NETs and SCLC to sorafenib, and could be repurposed as an adjuvant therapy with targeted agents that induce disruptions in thiol metabolism.
Asunto(s)
Auranofina , Neoplasias Pulmonares , Compuestos de Fenilurea , Carcinoma Pulmonar de Células Pequeñas , Sorafenib , Reductasa de Tiorredoxina-Disulfuro , Ensayos Antitumor por Modelo de Xenoinjerto , Auranofina/farmacología , Auranofina/uso terapéutico , Animales , Sorafenib/farmacología , Sorafenib/uso terapéutico , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidores , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Humanos , Ratones , Línea Celular Tumoral , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/uso terapéutico , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/metabolismo , Ratones Desnudos , Niacinamida/análogos & derivados , Niacinamida/farmacología , Niacinamida/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
Patients with rheumatoid arthritis (RA) who receive immunosuppressive medications have a heightened risk of infection. The goal of our study was to calculate the pooled cumulative incidence and risk of infection in patients with RA treated with Janus kinase inhibitors (JAKi). The PubMed and EMBASE databases were queried for randomized controlled trials comparing patients with RA treated with JAKi (upadacitinib, baricitinib, tofacitinib, peficitinib, or filgotinib), defined as the treatment group, compared with control subjects, defined as participants receiving placebo or treatment regimen that was similar to that of participants in the treatment group, with the exception of JAKi. The primary study endpoint was the relative risk (RR) of any-grade and severe infection. The secondary endpoints were RR and cumulative incidence of opportunistic infections, herpes zoster, and pneumonia. The Stata v17 software was used for all data analysis. Results showed that treatment with baricitinib was associated with an increased risk of any-grade (RR 1.34; 95% CI: 1.19-1.52) and opportunistic (RR 2.69; 95% CI: 1.22-5.94) infection, whereas treatment with filgotinib (RR 1.21; 95% CI: 1.05-1.39), peficitinib (RR 1.40; 95% CI: 1.05-1.86) and upadacitinib (RR 1.30; 95% CI: 1.09-1.56) was associated with increased risk of any-grade infection only. Analysis based on type of infection showed a pooled cumulative incidence of 32.44% for any-grade infections, 2.02% for severe infections, 1.74% for opportunistic infections, 1.56% for herpes zoster, and 0.49% for pneumonia in patients treated with any JAKi during the follow-up period. Treatment with specific JAKi in patients with RA is associated with an increased risk of any-grade and opportunistic infections but not severe infection. Close clinical monitoring of patients with RA treated with JAKi is required to establish the long-term infection risk profile of these agents.
Asunto(s)
Artritis Reumatoide , Azetidinas , Inhibidores de las Cinasas Janus , Piperidinas , Purinas , Pirazoles , Pirimidinas , Sulfonamidas , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/complicaciones , Humanos , Inhibidores de las Cinasas Janus/efectos adversos , Inhibidores de las Cinasas Janus/uso terapéutico , Azetidinas/efectos adversos , Azetidinas/uso terapéutico , Incidencia , Purinas/efectos adversos , Purinas/uso terapéutico , Pirazoles/efectos adversos , Pirazoles/uso terapéutico , Pirimidinas/efectos adversos , Pirimidinas/uso terapéutico , Piperidinas/efectos adversos , Piperidinas/uso terapéutico , Sulfonamidas/efectos adversos , Sulfonamidas/uso terapéutico , Herpes Zóster/epidemiología , Herpes Zóster/inducido químicamente , Infecciones Oportunistas/epidemiología , Infecciones Oportunistas/inducido químicamente , Pirroles/efectos adversos , Pirroles/uso terapéutico , Niacinamida/análogos & derivados , Niacinamida/efectos adversos , Niacinamida/uso terapéutico , Infecciones/epidemiología , Infecciones/inducido químicamente , Ensayos Clínicos Controlados Aleatorios como Asunto , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Antirreumáticos/efectos adversos , Antirreumáticos/uso terapéutico , Triazoles/efectos adversos , Triazoles/uso terapéutico , Adamantano/análogos & derivados , PiridinasRESUMEN
Nicotinamide adenine dinucleotide (NAD +) plays a pivotal role in numerous cellular functions. Reduced NAD + levels are postulated to be associated with cancer. As interest in understanding NAD + dynamics in cancer patients with therapeutic applications in mind grows, there remains a shortage of comprehensive data. This study delves into NAD + dynamics in patients undergoing surgery for different digestive system cancers. This prospective study enrolled 99 patients with eight different cancers. Fasting blood samples were obtained during the perioperative period. The concentrations of NAD + , nicotinamide mononucleotide (NMN), and nicotinamide riboside were analyzed using tandem mass spectrometry. After erythrocyte volume adjustment, NAD + remained relatively stable after surgery. Meanwhile, NMN decreased the day after surgery and displayed a recovery trend. Interestingly, liver and pancreatic cancer patients exhibited poor postoperative NMN recovery, suggesting a potential cancer type-specific influence on NAD + metabolism. This study illuminated the behavior of NAD + in surgically treated cancer patients. We identified which cancer types have particularly low levels and at what point depletion occurs during the perioperative period. These insights suggest the need for personalized NAD + supplementation strategies, calibrated to individual patient needs and treatment timelines. Clinical trial registration jRCT1020210066.
Asunto(s)
NAD , Niacinamida , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , NAD/metabolismo , Neoplasias/cirugía , Neoplasias/metabolismo , Niacinamida/uso terapéutico , Niacinamida/metabolismo , Niacinamida/análogos & derivados , Mononucleótido de Nicotinamida/metabolismo , Estudios Prospectivos , Compuestos de Piridinio , Espectrometría de Masas en TándemRESUMEN
Skin aging has long been considered a purely cosmetic problem. However, as life expectancy increases, skin aging is taking on a functional dimension that goes beyond cosmetics and appearance. Preventive or therapeutic strategies are needed to target cellular senescence, a key process underlying the alterations in skin function and appearance that occur with aging, as well as to address the age-related skin changes associated with 'dermatoporosis' and chronic skin insufficiency/fragility syndrome. Thus, given the need for effective anti-aging products that improve both the appearance and function of the skin, it is essential to distinguish active ingredients that have been proven to be effective, among the large number of available over-the-counter cosmeceuticals. This brief review focuses on a core group of topical actives, describing their clinical effects on senescence and aging, and their molecular mechanisms of action. These actives include hyaluronic acid, which has hydrating and viscoelastic properties and has been shown to reduce skin atrophy; retinaldehyde, which activates retinoid receptors and increases cutaneous elasticity; vitamins C and E, which provide stable oxidative protection; and niacinamide, which reduces inflammation and mitigates the effects of senescence.
Asunto(s)
Senescencia Celular , Envejecimiento de la Piel , Envejecimiento de la Piel/efectos de los fármacos , Envejecimiento de la Piel/fisiología , Humanos , Senescencia Celular/efectos de los fármacos , Ácido Hialurónico/farmacología , Ácido Ascórbico/farmacología , Ácido Ascórbico/uso terapéutico , Niacinamida/farmacología , Niacinamida/uso terapéutico , Vitamina E/farmacología , Cosmecéuticos/farmacología , Piel/patología , Piel/efectos de los fármacosRESUMEN
Aim: Bullous pemphigoid induced by secukinumab in treatment of psoriasis is rare.Methods: We report a 49-year-old man with psoriasis who developed bullous pemphigoid during treatment with secukinumab.Results: Scattered tense vesicles with itching appeared all over the body after the fourth treatment. Bullous pemphigoid was confirmed by pathological examination and direct immunofluorescence. The patient was treated with topical corticosteroids, oral nicotinamide and minocycline hydrochloride. The lesions of bullous pemphigoid improved significantly after 7 days of treatment.Conclusions: Bullous pemphigoid is a rare adverse event following administration of secukinumab.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Penfigoide Ampolloso , Psoriasis , Humanos , Penfigoide Ampolloso/inducido químicamente , Penfigoide Ampolloso/tratamiento farmacológico , Penfigoide Ampolloso/patología , Penfigoide Ampolloso/diagnóstico , Masculino , Persona de Mediana Edad , Anticuerpos Monoclonales Humanizados/efectos adversos , Psoriasis/tratamiento farmacológico , Psoriasis/inducido químicamente , Minociclina/efectos adversos , Niacinamida/análogos & derivados , Niacinamida/efectos adversos , Niacinamida/uso terapéutico , Fármacos Dermatológicos/efectos adversos , Resultado del TratamientoRESUMEN
OBJECTIVE: This study aims to evaluate the efficacy and safety of JAK inhibitors in the treatment of patients with RA. METHODS: The databases CNKI, VIP, Wanfang, CBM, and PubMed, Embase, Cochrane Library and Web of Science were searched to identify relevant randomized controlled trials (RCTs), all from the time of database creation to April 2024. Screening, data extraction, and risk of bias assessment (using Review Manager-5.3 software) were independently performed by at least two authors. The network meta-analysis was conducted using R 4.1.3 software. PROSPERO registration number: CRD42022370444. RESULTS: Thirty-three RCTs included 15,961 patients The experimental groups involved six JAK inhibitors (filgotinib, tofacitinib, decernotinib, baricitinib, upadacitinib and peficitinib) and 12 interventions (different doses of the six JAK inhibitors), and the control group involved adalimumab (ADA) and placebo. Compared with placebo, all JAK inhibitors showed a significant increase in efficacy measures (ACR20/50/70). Compared with ADA, only tofacitinib, low-dose decernotinib, and high-dose peficitinib showed a significant increase in ACR20/50/70. Decernotinib ranked first in the SUCRA ranking of ACR20/50/70. In terms of safety indicators, only those differences between low-dose filgotinib and high-dose upadacitinib, low-dose tofacitinib and high-dose upadacitinib were statistically significant. Low-dose filgotinib ranked first in the SUCRA ranking with adverse events as safety indicators. Only the efficacy and safety of tofacitinib ranked higher among different SUCRA rankings. CONCLUSION: Six JAK inhibitors have better efficacy than placebo. The superior efficacy of decernotinib and safety of low-dose filgotinib can be found in the SUCRA. However, there are no significant differences in safety between the different JAK inhibitors. Head-to-head trials, directly comparing one against each other, are required to provide more certain evidence.
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Artritis Reumatoide , Azetidinas , Teorema de Bayes , Inhibidores de las Cinasas Janus , Metaanálisis en Red , Piperidinas , Pirimidinas , Humanos , Artritis Reumatoide/tratamiento farmacológico , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de las Cinasas Janus/efectos adversos , Pirimidinas/uso terapéutico , Pirimidinas/efectos adversos , Piperidinas/uso terapéutico , Piperidinas/efectos adversos , Azetidinas/uso terapéutico , Azetidinas/efectos adversos , Purinas/uso terapéutico , Purinas/efectos adversos , Pirroles/uso terapéutico , Pirroles/efectos adversos , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Sulfonamidas/uso terapéutico , Sulfonamidas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Compuestos Heterocíclicos con 2 Anillos/uso terapéutico , Compuestos Heterocíclicos con 2 Anillos/efectos adversos , Niacinamida/análogos & derivados , Niacinamida/uso terapéutico , Niacinamida/efectos adversos , Benzamidas/uso terapéutico , Benzamidas/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Antirreumáticos/uso terapéutico , Antirreumáticos/efectos adversos , Triazoles/uso terapéutico , Triazoles/efectos adversos , Triazoles/administración & dosificación , Adamantano/análogos & derivados , Piridinas , Valina/análogos & derivadosRESUMEN
People with lower extremity peripheral artery disease (PAD) have increased oxidative stress, impaired mitochondrial activity, and poor walking performance. NAD+ reduces oxidative stress and is an essential cofactor for mitochondrial respiration. Oral nicotinamide riboside (NR) increases bioavailability of NAD+ in humans. Among 90 people with PAD, this randomized double-blind clinical trial assessed whether 6-months of NR, with and without resveratrol, improves 6-min walk distance, compared to placebo, at 6-month follow-up. At 6-month follow-up, compared to placebo, NR significantly improved 6-min walk (+7.0 vs. -10.6 meters, between group difference: +17.6 (90% CI: + 1.8,+∞). Among participants who took at least 75% of study pills, compared to placebo, NR improved 6-min walk by 31.0 meters and NR + resveratrol improved 6-min walk by 26.9 meters. In this work, NR meaningfully improved 6-min walk, and resveratrol did not add benefit to NR alone in PAD. A larger clinical trial to confirm these findings is needed.
Asunto(s)
Niacinamida , Enfermedad Arterial Periférica , Compuestos de Piridinio , Resveratrol , Humanos , Enfermedad Arterial Periférica/tratamiento farmacológico , Niacinamida/análogos & derivados , Niacinamida/uso terapéutico , Masculino , Femenino , Anciano , Método Doble Ciego , Resveratrol/uso terapéutico , Resveratrol/farmacología , Persona de Mediana Edad , Caminata , Resultado del Tratamiento , Estrés Oxidativo/efectos de los fármacosRESUMEN
Nicotinamide riboside (NR) is a precursor and exogenous supplement of nicotinamide adenine dinucleotide (NAD+). NR has been shown to play a beneficial role in a variety of neurodegenerative diseases. A phase 1 clinical trial identified NR as a potential neuroprotective therapy for Parkinson's disease (PD). However, the mechanism of action of NR in PD has not been fully elucidated. Therefore, the present study aimed to investigate the potential effects of NR on a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model in zebrafish and its underlying mechanisms. The results showed that NR improved motor dysfunction, survival time, dopamine neurons, and peripheral neurons, as well as the NAD+ levels in the MPTP-affected PD zebrafish model. In addition, transcriptome sequencing analysis revealed that, after NR treatment, differentially expressed genes were significantly enriched in the glucose metabolism and protein processing pathways in the endoplasmic reticulum (ER). Quantitative PCR (qPCR) revealed that the mRNA levels of the glycoheterotrophic enzyme (involved in glucose metabolism) were significantly decreased, and the glycolytic enzyme mRNA expression levels were significantly increased. The results of the non-targeted metabolomic analysis showed that NR treatment significantly increased the levels of metabolites such as nicotinic acid ,nicotinamide, d-glucose (from the gluconeogenesis and glycolysis metabolism pathways) and some glucogenic amino acids, such as glutamine. Importantly, NR ameliorated MPTP-induced endoplasmic reticulum stress (ERS) in the PD zebrafish model through the Perk-Eif2α-Atf4-Chop pathway. These results highlight the neuroprotective effect of NR in the present PD zebrafish model through modulation of glucose metabolism and ERS via the Perk-Eif2α-Atf4-Chop pathway and provide valuable mechanistic insights into the treatment of PD.
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1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Modelos Animales de Enfermedad , Estrés del Retículo Endoplásmico , Glucosa , Niacinamida , Compuestos de Piridinio , Pez Cebra , Animales , Estrés del Retículo Endoplásmico/efectos de los fármacos , Niacinamida/análogos & derivados , Niacinamida/farmacología , Niacinamida/uso terapéutico , Compuestos de Piridinio/farmacología , Compuestos de Piridinio/uso terapéutico , Glucosa/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Actividad Motora/efectos de los fármacos , MasculinoRESUMEN
Nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) have received considerable attention as anti-aging and anti-metabolic disease nutraceuticals. However, few studies have focused on their role in ameliorating hepatic metabolic disturbances. In the present study, the effects of NMN and NR on the liver of mice with nonalcoholic fatty liver disease (NAFLD) were investigated via transcriptome and metabolome analyses. NMN and NR reduced body weight gain, improved glucose homeostasis, regulated plasma lipid levels, and ameliorated liver injury, oxidative stress, and lipid accumulation in mice with HFD-induced NAFLD. Integrated transcriptome and metabolome analyses indicated that NMN and NR altered the biosynthesis of unsaturated fatty acids, arachidonic acid metabolism, and linoleic acid metabolism pathways, increased saturated fatty acid (palmitic acid, stearate, and arachidic acid) content, and increased polyunsaturated fatty acid (linoleic acid and eicosapentaenoic acid) content. Quantitative reverse transcription PCR (qRT-PCR) showed that NMN and NR primarily promoted arachidonic acid and linoleic acid catabolism via cytochrome P450 (CYP450) enzymes. This study established a theoretical foundation for the potential use of NMN and NR in future clinical settings.
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Hígado , Metaboloma , Ratones Endogámicos C57BL , Niacinamida , Mononucleótido de Nicotinamida , Enfermedad del Hígado Graso no Alcohólico , Compuestos de Piridinio , Transcriptoma , Animales , Niacinamida/farmacología , Niacinamida/uso terapéutico , Niacinamida/análogos & derivados , Compuestos de Piridinio/farmacología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Mononucleótido de Nicotinamida/farmacología , Mononucleótido de Nicotinamida/uso terapéutico , Masculino , Transcriptoma/efectos de los fármacos , Metaboloma/efectos de los fármacos , Ratones , Hígado/metabolismo , Hígado/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Dieta Alta en Grasa/efectos adversosRESUMEN
BACKGROUND/AIM: Oral squamous cell carcinoma (OSCC) is characterized by early metastasis, clinical resistance and poor prognosis. Recently, we showed that aggressive OSCC cells co-express endothelial cell markers and can form tube-like structures, known as vasculogenic mimicry (VM), a process associated with poor prognosis in head and neck cancers. Given the limited success of current antiangiogenic therapy in treating OSCC, this study sought to explore the efficiency of these drugs in targeting an ex vivo model of VM. MATERIALS AND METHODS: OSCC cell lines from the tongue and floor of the mouth in addition to human endothelial cells were used. The treatments comprised a set of clinically relevant antiangiogenic drugs: sorafenib, sunitinib, and axitinib, which were administered in different doses. Multiple ex vivo approaches including cell tubulogenesis, proliferation, apoptosis, and migration assays were used. RESULTS: Although these drugs inhibited the formation of endothelial cell capillaries, they showed clear differential effects on OSCC cell-derived VM and cell morphology. Sorafenib inhibited the tubulogenesis of aggressive OSCC cells compared with the limited effect of sunitinib and axitinib. Furthermore, our data consistently demonstrated a preferential efficacy of certain drugs over others. Sorafenib and sunitinib exhibited anti-cancer effects on tumor cell proliferation, apoptosis, and cell migration, compared with the limited effect of axitinib. CONCLUSION: The antiangiogenic drugs, except sorafenib, had limited effect on VM formation in vitro and exhibited varying anti-cancer effects on OSCC cells. These data support the notion that VM formation may in part explain the development of drug resistance in OSCC cells.
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Inhibidores de la Angiogénesis , Axitinib , Movimiento Celular , Proliferación Celular , Neoplasias de la Boca , Neovascularización Patológica , Sorafenib , Sunitinib , Humanos , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/patología , Neoplasias de la Boca/irrigación sanguínea , Neoplasias de la Boca/metabolismo , Línea Celular Tumoral , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Sorafenib/farmacología , Sorafenib/uso terapéutico , Sunitinib/farmacología , Sunitinib/uso terapéutico , Proliferación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Axitinib/farmacología , Apoptosis/efectos de los fármacos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/irrigación sanguínea , Carcinoma de Células Escamosas/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Células Endoteliales/metabolismo , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/uso terapéutico , Niacinamida/análogos & derivados , Niacinamida/farmacología , Niacinamida/uso terapéuticoRESUMEN
PURPOSE: RUNX3 is a tumor suppressor gene, which is inactivated in approximately 70% of lung adenocarcinomas. Nicotinamide, a sirtuin inhibitor, has demonstrated potential in re-activating epigenetically silenced RUNX3 in cancer cells. This study assessed the therapeutic benefits of combining nicotinamide with first-generation EGFR-tyrosine kinase inhibitors (TKI) for patients with stage IV lung cancer carrying EGFR mutations. PATIENTS AND METHODS: We assessed the impact of nicotinamide on carcinogen-induced lung adenocarcinomas in mice and observed that nicotinamide increased RUNX3 levels and inhibited lung cancer growth. Subsequently, 110 consecutive patients with stage IV lung cancer who had EGFR mutations were recruited: 70 females (63.6%) and 84 never-smokers (76.4%). The patients were randomly assigned to receive either nicotinamide (1 g/day, n = 55) or placebo (n = 55). The primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS), respectively. RESULTS: After a median follow-up of 54.3 months, the nicotinamide group exhibited a median PFS of 12.7 months [95% confidence interval (CI), 10.4-18.3], while the placebo group had a PFS of 10.9 months (9.0-13.2; P = 0.2). The median OS was similar in the two groups (31.0 months with nicotinamide vs. 29.4 months with placebo; P = 0.2). Notably, subgroup analyses revealed a significant reduction in mortality risk for females (P = 0.01) and never-smokers (P = 0.03) treated with nicotinamide. CONCLUSIONS: The addition of nicotinamide with EGFR-TKIs demonstrated potential improvements in PFS and OS, with notable survival benefits for female patients and those who had never smoked (ClinicalTrials.gov Identifier: NCT02416739).
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Adenocarcinoma del Pulmón , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Femenino , Animales , Ratones , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Niacinamida/uso terapéutico , Pronóstico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Receptores ErbB/genéticaRESUMEN
BACKGROUND: Diabetes-related skin ulcers provide a substantial therapeutic issue, sometimes leading to amputation, needing immediate practical treatments for efficient wound care. While the exact mechanisms are unknown, pyroptosis and deregulation of the unfolded protein response (UPR) are known to exacerbate inflammation. Nicotinamide Riboside (NR) and Resveratrol (RV), which are known for their Nicotinamide adenine dinucleotide (NAD+) boosting and anti-inflammatory properties, are being studied as potential treatments. The purpose of this study was to shed light on the underlying molecular mechanisms and explore the medical application of NR and RV in diabetic wound healing. METHODS: 54 male Sprague-Dawley rats divided into control, diabetic (DM), Gel Base, DM-NR, DM-RV, and DM-NR + RV. Rats were orally administered 50 mg/kg/day of RV and 300 mg/kg/day of NR for 5 weeks. Following diabetes induction, their wounds were topically treated with 5 % NR and RV gel for 15 days. The wound closure rate, body weight, and serum lipid profiles were examined. Gene expression study evaluated UPR and pyroptosis-related genes (BIP, PERK, ATF6, IRE1α, sXBP1, CHOP, NLRP3, caspase-1, NFκB, and IL1-ß) in wound tissues, alongside histological assessment of cellular changes. RESULTS: NR and RV treatments greatly enhanced wound healing. Molecular investigation demonstrated UPR and pyroptosis marker modifications, suggesting UPR balance and anti-inflammatory effects. Histological investigation demonstrated decreased inflammation and increased re-epithelialization. The combination of NR and RV therapy had better results than either treatment alone. CONCLUSION: This study shows that NR and RV have therapeutic promise in treating diabetic wounds by addressing UPR dysregulation, and pyroptosis. The combination therapy is a viable strategy to improving the healing process, providing a multimodal intervention for diabetic skin ulcers. These findings pave the way for additional investigation and possible therapeutic applications, giving hope for better outcomes in diabetic wound care.
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Diabetes Mellitus Experimental , Niacinamida , Niacinamida/análogos & derivados , Compuestos de Piridinio , Piroptosis , Ratas Sprague-Dawley , Resveratrol , Respuesta de Proteína Desplegada , Cicatrización de Heridas , Animales , Masculino , Piroptosis/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacos , Resveratrol/farmacología , Resveratrol/uso terapéutico , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Niacinamida/uso terapéutico , Niacinamida/farmacología , Compuestos de Piridinio/uso terapéutico , Compuestos de Piridinio/farmacología , Respuesta de Proteína Desplegada/efectos de los fármacos , Ratas , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacologíaRESUMEN
PURPOSE OF REVIEW: Topical therapies are a mainstay of treatment for mild psoriasis and may be a useful adjunct in treatment of moderate-to-severe psoriasis. This review summarizes recent advances in topical therapies for psoriasis and currently available treatments. RECENT FINDINGS: Topical aryl hydrocarbon receptor modulators (tapinarof) and topical phosphodiesterase-4 inhibitors (roflumilast) have been proven effective in randomized controlled trials for psoriasis. Although topical JAK inhibitors have also been studied, none are currently licensed for treatment of psoriasis. Topical corticosteroids and vitamin D analogues remain the most commonly used and widely available topical treatments for psoriasis. Cost may limit use of novel topical agents. SUMMARY: Although the novel topical agents tapinarof and roflumilast are licensed for treatment of psoriasis by the FDA in the United States, they have not yet been licensed in Europe, and it remains to be seen whether they will be limited by cost.
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Aminopiridinas , Ciclopropanos , Inhibidores de Fosfodiesterasa 4 , Psoriasis , Humanos , Psoriasis/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 4/administración & dosificación , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Ciclopropanos/administración & dosificación , Ciclopropanos/uso terapéutico , Aminopiridinas/uso terapéutico , Aminopiridinas/administración & dosificación , Benzamidas/administración & dosificación , Benzamidas/uso terapéutico , Administración Tópica , Corticoesteroides/administración & dosificación , Corticoesteroides/uso terapéutico , Vitamina D/administración & dosificación , Vitamina D/uso terapéutico , Fármacos Dermatológicos/administración & dosificación , Fármacos Dermatológicos/uso terapéutico , Niacinamida/análogos & derivados , Niacinamida/administración & dosificación , Niacinamida/uso terapéutico , Resorcinoles , EstilbenosRESUMEN
INTRODUCTION: Ultraviolet radiation (UVR) is the primary risk factor for keratinocyte carcinomas. Oral supplementation with nicotinamide (NAM) is reported to reduce the formation of new keratinocyte carcinomas. NAM's photoprotection is mediated by enhanced DNA repair. We wanted to explore whether NAM in combination with antiproliferative (metformin [Met]) or antioxidant (phloroglucinol [PG]) compounds could potentially enhance its photoprotective effects. METHODS: Hairless mice (C3.Cg-Hrhr/TifBomTac) were treated orally with either a standard dose of NAM monotherapy (NAM-mono; 600 mg/kg) or NAM (400 mg/kg) combined with Met (200 mg/kg) (NAM-Met) or PG (75 mg/kg) (NAM-PG). Mice were irradiated with 3.5 standard erythema doses of UVR three times per week to induce tumour development. Photoprotective effects were based on (i) tumour onset of the first three tumours, (ii) skin photodamage, and (iii) DNA damage (cyclobutane pyrimidine dimers [CPDs] and pyrimidine-pyrimidone (6-4) photoproducts [6-4PPs]). RESULTS: All mice treated with NAM demonstrated a delay in tumour onset and reduced tumour burden compared to the UV control group (NAM, NAM-Met, NAM-PG vs. UV control: p ≤ 0.015). NAM-mono and NAM-PG increased time until all three tumours with no difference between them, indicating a similar degree of photoprotection. NAM-mono had no effect on DNA damage compared to the UV control group (p > 0.05), whereas NAM-PG reduced 6-4PP lesions (p < 0.01) but not CPDs (p > 0.05) compared to NAM-mono. NAM-Met delayed the onset of the third tumour compared to the UV control but demonstrated a quicker onset compared to NAM-mono, suggesting inferior photoprotection compared to nicotinamide monotherapy. CONCLUSION: NAM-PG was as effective in delaying UVR-induced tumour onset as NAM-mono. The reduction in 6-4PP lesions may indicate that the mechanism of NAM-PG is better suited for photoprotection than NAM-mono. NAM-mono was superior to NAM-Met, indicating a dose dependency of NAM's photoprotection. These results highlight the potential for combining photoprotective compounds to enhance photoprotection.
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Metformina , Ratones Pelados , Niacinamida , Neoplasias Cutáneas , Rayos Ultravioleta , Animales , Niacinamida/uso terapéutico , Niacinamida/farmacología , Neoplasias Cutáneas/prevención & control , Rayos Ultravioleta/efectos adversos , Ratones , Metformina/farmacología , Metformina/uso terapéutico , Neoplasias Inducidas por Radiación/prevención & control , Neoplasias Inducidas por Radiación/etiología , Quimioterapia Combinada , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Daño del ADN/efectos de los fármacos , Daño del ADN/efectos de la radiación , Femenino , Complejo Vitamínico B/uso terapéutico , Complejo Vitamínico B/farmacologíaRESUMEN
Peficitinib is a selective Janus kinase (JAK3) inhibitor recently developed and approved for the treatment of rheumatoid arthritis in Japan. Glycolysis in macrophages could induce NOD-like receptor (NLR) family and pyrin domain-containing protein 3 (NLRP3) inflammasome activation, thus resulting in pyroptosis and acute lung injury (ALI). The aim of our study was to investigate whether Peficitinib could alleviate lipopolysaccharide (LPS)-induced ALI by inhibiting NLRP3 inflammasome activation. Wild type C57BL/6J mice were intraperitoneally injected with Peficitinib (5 or 10 mg·kg-1·day-1) for 7 consecutive days before LPS injection. The results showed that Peficitinib pretreatment significantly relieved LPS-induced pulmonary edema, inflammation, and apoptosis. NLRP3 inflammasome and glycolysis in murine lung tissues challenged with LPS were also blocked by Peficitinib. Furthermore, we found that the activation of JAK3/signal transducer and activator of transcription 3 (STAT3) was also suppressed by Peficitinib in mice with ALI. However, in Jak3 knockout mice, Peficitinib did not show obvious protective effects after LPS injection. In vitro experiments further showed that Jak3 overexpression completely abolished Peficitinib-elicited inhibitory effects on pyroptosis and glycolysis in LPS-induced RAW264.7 macrophages. Finally, we unveiled that LPS-induced activation of JAK3/STAT3 was mediated by toll-like receptor 4 (TLR4) in RAW264.7 macrophages. Collectively, our study proved that Peficitinib could protect against ALI by blocking JAK3-mediated glycolysis and pyroptosis in macrophages, which may serve as a promising candidate against ALI in the future.
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Lesión Pulmonar Aguda , Adamantano/análogos & derivados , Glucólisis , Janus Quinasa 3 , Lipopolisacáridos , Ratones Endogámicos C57BL , Niacinamida , Niacinamida/análogos & derivados , Factor de Transcripción STAT3 , Transducción de Señal , Animales , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/metabolismo , Janus Quinasa 3/metabolismo , Janus Quinasa 3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Glucólisis/efectos de los fármacos , Ratones , Transducción de Señal/efectos de los fármacos , Masculino , Niacinamida/farmacología , Niacinamida/uso terapéutico , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ratones Noqueados , Acrilamidas/farmacología , Acrilamidas/uso terapéutico , Inflamasomas/metabolismo , Piroptosis/efectos de los fármacos , Pulmón/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/inmunologíaRESUMEN
PURPOSE: To investigate the effect of nicotinamide (Nam) on diabetic kidney disease (DKD) in mice and explore its mechanism. METHODS: Thirty DBA/2 J mice were randomly assigned to three groups. After 8 weeks of hyperglycemia induced by streptozocin (STZ), Nam and saline were administrated to STZ + Nam and STZ + NS mice, respectively, for 8 weeks. Non-diabetic mice (NDM) were used as control group. Twenty In2-/- Akita mice were randomly divided into two groups. After 8 weeks of hyperglycemia, Nam and saline were administered to Akita + Nam and Akita + NS mice, respectively, for 6 weeks. Wild-type littermates were used as control group. Markers of renal injury were analyzed, and the molecular mechanisms were explored in human proximal tubular HK2 cells. RESULTS: Urinary albumin-to-creatinine ratio (UACR) and kidney injury molecule 1 (KIM-1) decreased in the STZ + Nam and Akita + Nam groups. Pathological analysis showed that Nam improved the structure of glomerular basement membrane, ameliorated glomerular sclerosis, and decreased the accumulation of extracellular matrix and collagen. Compared to the diabetic control group, renal fibrosis, inflammation, and oxidative stress were reduced in the Nam-treated mice. The expression of sirtuin 1 (Sirt1) in human proximal tubular HK2 cells was inhibited by high glucose and Nam treatment enhanced its expression. However, in HK2 cells with Sirt1 knockdown, the protective effect of Nam was abolished, indicating that the beneficial effect of Nam was partially dependent on Sirt1. CONCLUSIONS: Nam has a renoprotective effect against renal injury caused by hyperglycemia and may be a potential target for the treatment of DKD.