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1.
J Am Coll Cardiol ; 78(16): 1635-1654, 2021 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-34649702

RESUMO

Coronavirus disease-2019 (COVID-19) is associated with systemic inflammation, endothelial activation, and multiorgan manifestations. Lipid-modulating agents may be useful in treating patients with COVID-19. These agents may inhibit viral entry by lipid raft disruption or ameliorate the inflammatory response and endothelial activation. In addition, dyslipidemia with lower high-density lipoprotein cholesterol and higher triglyceride levels portend worse outcomes in patients with COVID-19. Upon a systematic search, 40 randomized controlled trials (RCTs) with lipid-modulating agents were identified, including 17 statin trials, 14 omega-3 fatty acids RCTs, 3 fibrate RCTs, 5 niacin RCTs, and 1 dalcetrapib RCT for the management or prevention of COVID-19. From these 40 RCTs, only 2 have reported preliminary results, and most others are ongoing. This paper summarizes the ongoing or completed RCTs of lipid-modulating agents in COVID-19 and the implications of these trials for patient management.


Assuntos
COVID-19/tratamento farmacológico , COVID-19/prevenção & controle , Ácidos Graxos Ômega-3/uso terapêutico , Ácidos Fíbricos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Niacina/uso terapêutico , Amidas/farmacologia , Amidas/uso terapêutico , Ésteres/farmacologia , Ésteres/uso terapêutico , Ácidos Graxos Ômega-3/farmacologia , Ácidos Fíbricos/farmacologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Reguladores do Metabolismo de Lipídeos/farmacologia , Reguladores do Metabolismo de Lipídeos/uso terapêutico , Niacina/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Compostos de Sulfidrila/farmacologia , Compostos de Sulfidrila/uso terapêutico
2.
Plant Mol Biol ; 107(1-2): 63-84, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34460049

RESUMO

KEY MESSAGE: Overexpressing Nicotinamidase 3 gene, and the exogenous application of its metabolite nicotinic acid (NA), enhance drought stress tolerance and increase biomass in Arabidopsis thaliana. With progressive global climatic changes, plant productivity is threatened severely by drought stress. Deciphering the molecular mechanisms regarding genes responsible for balancing plant growth and stress amelioration could imply multiple possibilities for future sustainable goals. Nicotinamide adenine dinucleotide (NAD) biosynthesis and recycling/ distribution is a crucial feature for plant growth. The current study focuses on the functional characterization of nicotinamidase 3 (NIC3) gene, which is involved in the biochemical conversion of nicotinamide (NAM) to nicotinic acid (NA) in the salvage pathway of NAD biosynthesis. Our data show that overexpression of NIC3 gene enhances drought stress tolerance and increases plant growth. NIC3-OX plants accumulated more NA as compared to WT plants. Moreover, the upregulation of several genes related to plant growth/stress tolerance indicates that regulating the NAD salvage pathway could significantly enhance plant growth and drought stress tolerance. The exogenous application of nicotinic acid (NA) showed a similar phenotype as the effect of overexpressing NIC3 gene. In short, we contemplated the role of NIC3 gene and NA application in drought stress tolerance and plant growth. Our results would be helpful in engineering plants with enhanced drought stress tolerance and increased growth potential.


Assuntos
Adaptação Fisiológica/genética , Proteínas de Arabidopsis/genética , Arabidopsis/fisiologia , Biomassa , Secas , Genes de Plantas , Niacina/farmacologia , Nicotinamidase/genética , Adaptação Fisiológica/efeitos dos fármacos , Arabidopsis/efeitos dos fármacos , Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Modelos Biológicos , NAD/metabolismo , NADP/metabolismo , Nicotinamidase/metabolismo , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/fisiologia , Brotos de Planta/efeitos dos fármacos , Brotos de Planta/fisiologia , Plantas Geneticamente Modificadas , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genética , Transcriptoma/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
4.
J Agric Food Chem ; 69(23): 6423-6430, 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34085526

RESUMO

Nicotinic acid, also known as niacin, is a natural product, which is widely found in plants and animals. To discover novel natural-product-based herbicides, a series of N-(arylmethoxy)-2-chloronicotinamides were designed and synthesized. Some of the new N-(arylmethoxy)-2-chloronicotinamides exhibited excellent herbicidal activity against Agrostis stolonifera (bentgrass) at 100 µM. Compound 5f (2-chloro-N-((3,4-dichlorobenzyl)oxy)nicotinamide) possessed excellent herbicidal activity against Lemna paucicostata (duckweed), with an IC50 value of 7.8 µM, whereas the commercial herbicides clomazone and propanil had values of 125 and 2 µM, respectively. The structure-activity relationships reported in this paper could be used for the development of new herbicides against monocotyledonous weeds.


Assuntos
Herbicidas , Niacina , Herbicidas/farmacologia , Niacina/farmacologia , Niacinamida/análogos & derivados , Plantas Daninhas , Relação Estrutura-Atividade
5.
Nutrients ; 13(5)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34068917

RESUMO

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


Assuntos
Antineoplásicos/farmacologia , NAD/biossíntese , NAD/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Vias Biossintéticas , Morte Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Citocinas , Dano ao DNA , Reparo do DNA , Humanos , Niacina/farmacologia , Niacinamida/farmacologia , Nicotinamida Fosforribosiltransferase , Estresse Oxidativo
6.
Theriogenology ; 169: 36-46, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33932650

RESUMO

Niacin, also known as vitamin B3, has a pivotal role in energy metabolism, cellular signaling cascades regulating gene expression, and apoptosis. However, the effect of Niacin on porcine early embryo developmental competence remains to be elucidated. The present study aimed to assess the effects of Niacin treatment during in vitro maturation (IVM) on the nuclear maturation of porcine oocytes and subsequent development of in vitro embryos. In addition, the expression profiles of selected genes related to lipid metabolism, oxidative stress, and apoptosis were assessed. The IVM medium was supplemented with different concentrations of Niacin (0, 300, 600, and 900 µM). The results showed that a high concentration of Niacin (900 µM) significantly decreased cumulus expansion compared to the other groups (p < 0.05). No significant difference was observed among the experimental groups for nuclear maturation rate. Niacin treatments (300, 600, and 900 µM) during IVM significantly (p < 0.05) enhanced glutathione levels. Treatment with 300 and 600 µM significantly (p < 0.05) lowered the reactive oxygen species levels compared to treatment with 900 µM and the control group. Niacin supplementation to the IVM media significantly improved the cleavage and blastocyst rates compared to the control group. Supplementation with 300 and 600 µM of Niacin significantly increased the total cell number of blastocysts compared to supplementation with 900 µM or the control groups. Cytoplasmic lipid droplets were significantly reduced after 600 µM treatment. Supplementation of Niacin to IVM media positively affected the relative expression of genes related to energy and oxidative status (SIRT1), pro-apoptosis (BAX), anti-apoptosis (BCL2), and lipid metabolism (ACACA and PNPLA2) in cumulus cells and oocytes. Taken together, Niacin supplementation to porcine IVM media improved the developmental competence of early embryos mainly through protection against oxidative stress and its influence on energy metabolism and apoptosis pathways.


Assuntos
Técnicas de Maturação in Vitro de Oócitos , Niacina , Animais , Blastocisto , Suplementos Nutricionais , Desenvolvimento Embrionário , Técnicas de Maturação in Vitro de Oócitos/veterinária , Niacina/farmacologia , Oócitos , Partenogênese , Suínos
7.
Int J Mol Sci ; 22(8)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33924461

RESUMO

Signaling through GPR109a, the putative receptor for the endogenous ligand ß-OH butyrate, inhibits adipose tissue lipolysis. Niacin, an anti-atherosclerotic drug that can induce insulin resistance, activates GPR109a at nM concentrations. GPR109a is not essential for niacin to improve serum lipid profiles. To better understand the involvement of GPR109a signaling in regulating glucose and lipid metabolism, we treated GPR109a wild-type (+/+) and knockout (-/-) mice with repeated overnight injections of saline or niacin in physiological states characterized by low (ad libitum fed) or high (16 h fasted) concentrations of the endogenous ligand, ß-OH butyrate. In the fed state, niacin increased expression of apolipoprotein-A1 mRNA and decreased sterol regulatory element-binding protein 1 mRNA independent of genotype, suggesting a possible GPR109a independent mechanism by which niacin increases high-density lipoprotein (HDL) production and limits transcriptional upregulation of lipogenic genes. Niacin decreased fasting serum non-esterified fatty acid concentrations in both GPR109a +/+ and -/- mice. Independent of GPR109a expression, niacin blunted fast-induced hepatic triglyceride accumulation and peroxisome proliferator-activated receptor α mRNA expression. Although unaffected by niacin treatment, fasting serum HDL concentrations were lower in GPR109a knockout mice. Surprisingly, GPR109a knockout did not affect glucose or lipid homeostasis or hepatic gene expression in either fed or fasted mice. In turn, GPR109a does not appear to be essential for the metabolic response to the fasting ketogenic state or the acute effects of niacin.


Assuntos
Jejum , Comportamento Alimentar , Fígado/metabolismo , Niacina/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Animais , Colesterol/metabolismo , Comportamento Alimentar/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Glicogênio/metabolismo , Homeostase/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Camundongos Knockout , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais/efeitos dos fármacos
8.
Int Immunopharmacol ; 95: 107584, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33756224

RESUMO

The objective was to evaluate the effects of niacin on intestinal immunity, microbial community and intestinal barrier in weaned piglets during starvation. In this study, twelve weaned piglets with similar body weight were randomly divided into two groups, six for each group. These piglets were treated with starvation, one group was treated with10 ml normal saline (Control), and the other group was perfused with 10 ml niacin solution (Niacin, 40 mg niacin was dissolved in equal volume of normal saline) once daily for three consecutive days. The results showed that niacin effectively attenuated the weight loss and diarrhea index (P < 0.05) in weaned piglets; Niacin improved jejunal villous height and intestinal morphological score (P < 0.05); Additionally, niacin significantly increased the mRNA expression of antimicrobial peptide (pBD2 and PR39) in the jejunum (P < 0.05); Meanwhile, niacin significantly increased ZO-1 and Occludin expression in the jejunum (P < 0.05). Furthermore, niacin improved the microbiota and the concentrations of acetate (P < 0.05). Conversely, niacin decreased the ratios of propionate/acetate and butyrate/acetate in the colonic contents of weaned piglets (P < 0.05); Interestingly, niacin increased the protein expression of SIRT1 (P < 0.05) and inhibited the protein expression of HDAC7 (P < 0.05). In conclusion, niacin attenuated the weight loss and diarrhea, and improved the expression of antimicrobial peptides, and enhanced intestinal epithelial barrier function, and improved the microbiota in the colonic contents of weaned piglets, suggesting that niacin may be an effective way for weaned piglets to maintain the gut and overall health.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Niacina/farmacologia , Animais , Células Cultivadas , Colo/efeitos dos fármacos , Colo/microbiologia , Diarreia/imunologia , Diarreia/microbiologia , Diarreia/patologia , Diarreia/veterinária , Feminino , Histona Desacetilases/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Proteínas Citotóxicas Formadoras de Poros/genética , Sirtuína 1/metabolismo , Inanição/imunologia , Inanição/microbiologia , Inanição/patologia , Inanição/veterinária , Suínos , Desmame , Perda de Peso/efeitos dos fármacos
9.
Bioorg Chem ; 107: 104610, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33454504

RESUMO

Two novel series derived from nicotinic acid were synthesized and evaluated for their inhibitory activity against cyclooxygenases COX-1 and COX-2, and their selectivity indices were determined. Celecoxib, diclofenac and indomethacin were used as reference drugs. All compounds showed highly potent COX-2 inhibitory activity and higher selectivity towards COX-2 inhibition compared to indomethacin. In addition, these compounds except 3a showed clear preferential COX-2 over COX-1 inhibition compared to diclofenac. Compounds 3b, 3e, 4c and 4f showed COX-2 inhibitory activity equipotent to celecoxib. Compounds 4c and 4f demonstrated selectivity indices 1.8-1.9 fold higher than celecoxib. These two most potent and COX-2 selective compounds were further tested in vivo for anti-inflammatory activity by means of carrageenan induced rat paw edema method. Ulcerogenic activity with histopathological studies were performed. The results showed no ulceration, which implies their safe gastric profile. Compound 4f exhibited the most potent in vivo anti-inflammatory activity comparable to all reference drugs. Further, compounds 4c and 4f were investigated for their influence on certain inflammatory cytokines TNF-α and IL-1ß in addition to PEG2. The findings revealed that these candidates could be identified as promising potent anti-inflammatory agents. Molecular docking of 4c and 4f in the COX-2 active site was performed to rationalize their COX-2 inhibitory potency. The results were found to be in line with the biological findings as they exerted more favorable interactions compared to that of celecoxib, explaining their remarkable COX-2 inhibitory activity.


Assuntos
Anti-Inflamatórios/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Niacina/química , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antiulcerosos/síntese química , Antiulcerosos/metabolismo , Antiulcerosos/farmacologia , Antiulcerosos/uso terapêutico , Sítios de Ligação , Domínio Catalítico , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Diclofenaco/farmacologia , Diclofenaco/uso terapêutico , Dinoprostona/sangue , Desenho de Fármacos , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/patologia , Masculino , Simulação de Acoplamento Molecular , Niacina/metabolismo , Niacina/farmacologia , Ratos , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/patologia , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/sangue
10.
Neurotoxicology ; 82: 89-98, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33232743

RESUMO

We have previously shown that JM-20, a new chemical entity consisting of 1,5-benzodiazepine fused to a dihydropyridine moiety, protects against rotenone-induced neurotoxicity in an experimental model of Parkinson's disease (PD). The aim of this study was to investigate the effect of a novel hybrid molecule, named JM-20, in in vitro and in vivo models of PD induced by 6-hydroxydopamine (6-OHDA). PC-12 cells were exposed to 6-OHDA and treated with JM-20. Protection against mitochondrial damage induced by 6-OHDA was also investigated using isolated rat brain mitochondria. We found that JM-20 protected PC-12 cells against cytotoxicity induced by 6-OHDA and inhibited hydrogen peroxide generation, mitochondrial swelling and membrane potential dissipation. For in vivo experiments, adult male Wistar rats were lesioned in the substantia nigra pars compacta (SNpc) by 6-OHDA administration. JM-20 was orally administered (10, 20 or 40 mg/kg), intragastric via gavage, 24 h after surgery and daily for seven days. Treatment with JM-20 significantly reduced the percentage of motor asymmetry and increased vertical exploration. It improved the redox state of the SNpc and the striatal tissue of these animals. Also, JM-20 reduced glial fibrillary acidic protein overexpression and increased tyrosine hydroxylase-positive cell number, both in SNpc. Altogether, these results demonstrate that JM-20 is a potential neuroprotective agent against 6-OHDA-induced damage in both in vitro and in vivo models. The mechanism underlying JM-20 neuroprotection against 6-OHDA appears to be associated with the control of oxidative injury and mitochondrial impairment.


Assuntos
Antioxidantes/farmacologia , Benzodiazepinas/farmacologia , Encéfalo/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Niacina/análogos & derivados , Oxidopamina/toxicidade , Transtornos Parkinsonianos/tratamento farmacológico , Animais , Masculino , Mitocôndrias/metabolismo , Niacina/farmacologia , Teste de Campo Aberto/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Células PC12/efeitos dos fármacos , Transtornos Parkinsonianos/induzido quimicamente , Ratos , Ratos Wistar
11.
Brief Bioinform ; 22(2): 1279-1290, 2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33169132

RESUMO

OBJECTIVES: Patients with colorectal cancer (CRC) may be susceptible to the coronavirus disease-2019 (COVID-19). However, anti-CRC/COVID-19 treatment options are currently unavailable. Since niacin is a vitamin with cytoprotective and anti-inflammatory functions, this study aimed to evaluate the possible functional roles and underlying mechanisms of action of niacin as an anti-COVID-19 and -CRC therapy. INTERVENTIONS: We used a series of network pharmacology-based and computational analyses to understand and characterize the binding capacity, biological functions, pharmacological targets and therapeutic mechanisms of niacin in CRC/COVID-19. MEASUREMENTS AND MAIN RESULTS: We revealed the clinical characteristics of CRC patients and COVID-19 patients, including predisposing genes, survival rate and prognosis. Moreover, the results of molecular docking analysis indicated that niacin exerted effective binding capacity in COVID-19. Further, we disclosed the targets, biological functions and signaling pathways of niacin in CRC/COVID-19. The analysis indicated that niacin could help in treating CRC/COVID-19 through cytoprotection, enhancement of immunologic functions, inhibition of inflammatory reactions and regulation of cellular microenvironment. Furthermore, five core pharmacological targets of niacin in CRC/COVID-19 were also identified, including BCL2L1, PTGS2, IL1B, IFNG and SERPINE1. CONCLUSIONS: This study, for the first time, revealed the niacin-associated molecular functions and pharmacological targets for treating CRC/COVID-19, as COVID-19 remains a serious pandemic. But the findings were not validated in actual CRC patients infected with COVID-19, so further investigation is needed to confirm the potential use of niacin for treating CRC/COVID-19.


Assuntos
COVID-19/tratamento farmacológico , Biologia Computacional , Niacina/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Idoso , COVID-19/virologia , Neoplasias Colorretais/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Simulação de Acoplamento Molecular , Niacina/farmacologia
12.
J Med Chem ; 64(1): 861-870, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33378197

RESUMO

Retinoid X receptor (RXR) modulators (rexinoids) are considered to have therapeutic potential for multiple diseases, such as Alzheimer's disease and Parkinson's disease. To overcome various disadvantages of prior screening methods, we previously developed an RXR binding assay using a fluorescent RXR ligand, CU-6PMN (4). However, this ligand binds not only at the ligand-binding domain (LBD) but also at the dimer-dimer interface of hRXRα. Here, we present a new fluorescent RXR antagonist 6-[N-ethyl-N-(5-isobutoxy-4-isopropyl-2-(11-oxo-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f]pyrido[3,2,1-ij]quinoline-10-carboxamido)phenyl)amino]nicotinic acid (NEt-C343, 7), which emits strong fluorescence only when bound to the RXR-LBD. It allows us to perform a rapid, simple, and nonhazardous binding assay that does not require bound/free separation and uses a standard plate reader. The obtained Ki values of known compounds were correlated with the Ki values obtained using the standard [3H]9cis-retinoic acid assay. This assay should be useful for drug discovery as well as for research on endocrine disruptors, functional foods, and natural products.


Assuntos
Niacina/química , Receptores X de Retinoides/antagonistas & inibidores , Sítios de Ligação , Humanos , Cinética , Ligantes , Simulação de Acoplamento Molecular , Niacina/metabolismo , Niacina/farmacologia , Ligação Proteica , Receptores X de Retinoides/genética , Receptores X de Retinoides/metabolismo , Espectrometria de Fluorescência , Ativação Transcricional/efeitos dos fármacos
13.
Brain Res Bull ; 165: 185-197, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33096198

RESUMO

The present study examines the possible effect of the novel hybrid molecule JM-20 (3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-411-dihydro-1H-pyrido[2,3-b] [1,5] benzodiazepine) on pain-related behaviours in a persistent pain model (5% formalin test) and in the neutrophil migration events during the inflammatory process. It further introduces JM-20 in a chronic constriction injury (CCI) model to clarify the possible subjacent mechanisms with its consequent clinical relevance. A single administration of JM-20 (20 or 40 mg/kg, per os [p.o.]) decreased licking/biting exclusively in the tonic phase of the formalin test in a GABA/benzodiazepine (BZD) receptor antagonist flumazenil-sensitive manner. JM-20 reduced in vivo neutrophil migration, rolling and adhesion to the endothelium induced by intraperitoneal administration of carrageenan in mice. In addition, plasma extravasation and tumour necrosis factor alpha production in the peritoneal fluid were decreased. Treatment with JM-20 (20 mg/kg, p.o.) for 7 days after CCI reduced mechanical hypersensitivity in a NG-monomethyl-l-arginine (L-NMMA)/methylene blue/glibenclamide-sensitive manner. Histopathological signs of Wallerian degeneration (WD) of the sciatic nerve were also attenuated, as well as interleukin-1 beta release in the spinal cord. The nitrate/nitrite concentration was increased centrally and did not show differences at the peripheral nerve level. The findings of this study suggest JM-20 can decrease persistent pain. A transient activity of its BDZ portion on nociceptive pathways mediated by GABA/BDZ receptors in association with its anti-inflammatory properties could be at least partially involved in this effect. JM-20 decreased CCI-induced mechanical hypersensitivity via the l-arginine/nitric oxide (NO)/cyclic GMP-sensitive ATP-sensitive potassium channel pathway. Its neuroprotective ability by preventing WD could be implicated in its anti-neuropathic mechanisms.


Assuntos
Benzodiazepinas/uso terapêutico , Inflamação/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Niacina/análogos & derivados , Dor/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Benzodiazepinas/farmacologia , Movimento Celular/efeitos dos fármacos , Inflamação/patologia , Masculino , Fármacos Neuroprotetores/farmacologia , Neutrófilos/efeitos dos fármacos , Niacina/farmacologia , Niacina/uso terapêutico , Dor/patologia , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia
14.
J Equine Vet Sci ; 94: 103236, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33077098

RESUMO

In the present study, we aimed to evaluate the possible protective effects of the nicotinic acid (NA) at three concentrations (10, 20, and 40 mM) on the equine cooled and frozen-thawed spermatozoa quality markers including viability, plasma membrane or acrosome integrity, DNA fragmentation, lipid peroxidation, and total oxidant levels. We also evaluated the effects of NA on preservation of the post-thaw sperm quality after 6 hours of cold storage before freezing. Five stallions were used for semen collections. The current experiment was repeated six times using pooled semen samples from two stallions, each time. We showed that NA at 20 and 40 mM concentrations could significantly improve the stallion sperm quality markers during cold storage. However, the protective effects were not different between 20 mM and 40 mM concentrations in most measures. Nicotinic acid could also improve the post-thaw stallion sperm quality at 10, 20, and 40 mM concentrations. However, the 40 mM concentration showed a negative impact on some post-thaw kinematic sperm parameters. Nicotinic acid at 10 and 20 mM concentrations could preserve the sperm cryo-tolerance to be frozen up to 8 hours after collection without a significant decline in most of the post-thaw sperm quality measures. Nicotinic acid could also decrease the level of the lipid peroxidation and total reactive oxygen/nitrogen species in the cooled and frozen-thawed spermatozoa, in a dose-dependent manner. Therefore, NA at 20 mM concentration could preserve most of the stallion sperm quality measures during cold storage (42 hours, 5°C) and enabled storage of cooled stallion semen for 6 hours before freezing without significant deterioration of the post-thaw sperm quality.


Assuntos
Niacina , Preservação do Sêmen , Animais , Suplementos Nutricionais , Congelamento , Cavalos , Masculino , Niacina/farmacologia , Sêmen , Preservação do Sêmen/veterinária
15.
Circ Res ; 127(10): 1323-1336, 2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-32912104

RESUMO

RATIONALE: Pulmonary arterial hypertension (PAH) is characterized by progressive pulmonary vascular remodeling, accompanied by varying degrees of perivascular inflammation. Niacin, a commonly used lipid-lowering drug, possesses vasodilating and proresolution effects by promoting the release of prostaglandin D2 (PGD2). However, whether or not niacin confers protection against PAH pathogenesis is still unknown. OBJECTIVE: This study aimed to determine whether or not niacin attenuates the development of PAH and, if so, to elucidate the molecular mechanisms underlying its effects. METHODS AND RESULTS: Vascular endothelial growth factor receptor inhibitor SU5416 and hypoxic exposure were used to induce pulmonary hypertension (PH) in rodents. We found that niacin attenuated the development of this hypoxia/SU5416-induced PH in mice and suppressed progression of monocrotaline-induced and hypoxia/SU5416-induced PH in rats through the reduction of pulmonary artery remodeling. Niacin boosted PGD2 generation in lung tissue, mainly through H-PGDS (hematopoietic PGD2 synthases). Deletion of H-PGDS, but not lipocalin-type PGDS, exacerbated the hypoxia/SU5416-induced PH in mice and abolished the protective effects of niacin against PAH. Moreover, H-PGDS was expressed dominantly in infiltrated macrophages in lungs of PH mice and patients with idiopathic PAH. Macrophage-specific deletion of H-PGDS markedly decreased PGD2 generation in lungs, aggravated hypoxia/SU5416-induced PH in mice, and attenuated the therapeutic effect of niacin on PAH. CONCLUSIONS: Niacin treatment ameliorates the progression of PAH through the suppression of vascular remodeling by stimulating H-PGDS-derived PGD2 release from macrophages.


Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão Pulmonar/tratamento farmacológico , Hipolipemiantes/farmacologia , Macrófagos/efeitos dos fármacos , Niacina/farmacologia , Animais , Anti-Hipertensivos/uso terapêutico , Células Cultivadas , Humanos , Hipertensão Pulmonar/metabolismo , Hipolipemiantes/uso terapêutico , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Macrófagos/metabolismo , Camundongos , Niacina/uso terapêutico , Prostaglandina D2/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Ratos
16.
PLoS One ; 15(9): e0227397, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32925921

RESUMO

The continuous and sole dependence on imidazolinone (IMI) herbicides for weedy rice control has led to the evolution of herbicide resistance in weedy rice populations across various countries growing IMI herbicide-resistant rice (IMI-rice), including Malaysia. A comprehensive study was conducted to elucidate occurrence, level, and mechanisms endowing resistance to IMI herbicides in putative resistant (R) weedy rice populations collected from three local Malaysian IMI-rice fields. Seed bioassay and whole-plant dose-response experiments were conducted using commercial IMI herbicides. Based on the resistance index (RI) quantification in both experiments, the cross-resistance pattern of R and susceptible (S) weedy rice populations and control rice varieties (IMI-rice variety MR220CL2 and non-IMI-rice variety MR219) to imazapic and imazapyr was determined. A molecular investigation was carried out by comparing the acetohydroxyacid synthase (AHAS) gene sequences of the R and S populations and the MR220CL2 and MR219 varieties. The AHAS gene sequences of R weedy rice were identical to those of MR220CL2, exhibiting a Ser-653-Asn substitution, which was absent in MR219 and S plants. In vitro assays were conducted using analytical grade IMI herbicides of imazapic (99.3%) and imazapyr (99.6%) at seven different concentrations. The results demonstrated that the AHAS enzyme extracted from the R populations and MR220CL2 was less sensitive to IMI herbicides than that from S and MR219, further supporting that IMI herbicide resistance was conferred by target-site mutation. In conclusion, IMI resistance in the selected populations of Malaysian weedy rice could be attributed to a Ser-653-Asn mutation that reduced the sensitivity of the target site to IMI herbicides. To our knowledge, this study is the first to show the resistance mechanism in weedy rice from Malaysian rice fields.


Assuntos
Acetolactato Sintase/genética , Resistência a Herbicidas/genética , Oryza/efeitos dos fármacos , Proteínas de Plantas/genética , Plantas Daninhas/efeitos dos fármacos , Acetoína/análise , Acetoína/metabolismo , Acetolactato Sintase/metabolismo , Substituição de Aminoácidos , Asparagina/genética , Bioensaio , Análise Mutacional de DNA , DNA de Plantas/genética , DNA de Plantas/isolamento & purificação , Ensaios Enzimáticos , Herbicidas/farmacologia , Imidazóis/farmacologia , Lactatos/metabolismo , Malásia , Mutação , Niacina/análogos & derivados , Niacina/farmacologia , Ácidos Nicotínicos/farmacologia , Oryza/genética , Proteínas de Plantas/metabolismo , Plantas Daninhas/genética , Sementes/efeitos dos fármacos , Serina/análise , Serina/genética , Serina/metabolismo , Controle de Plantas Daninhas/métodos
17.
Life Sci ; 260: 118415, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32918974

RESUMO

AIMS: Previous studies have shown the effect of niacin on dairy cow production, but no study on the role of niacin in milk fat synthesis has been performed. Therefore, the purpose of this study was to examine the effect of niacin on milk fat synthesis and its specific mechanism in BMECs. MAIN METHODS: In this study, 0.5 mM niacin, a GPR109A-inhibiting plasmid, and an AMPK inhibitor were added to BMECs. Milk fat was measured by a triglyceride kit and BODIPY staining. The protein expression of GPR109A, FASN, SREBP1, AMPK, ACC, mTOR and S6K was measured by Western blotting. The gene expression of GPR109A, FASN, and SREBP1 was analysed by RT-PCR. KEY FINDINGS: Our results showed that 0.5 mM niacin could significantly reduce milk fat synthesis in BMECs and activate the AMPK/ACC signalling pathway by stimulating GPR109A, reducing the protein expression of p-mTOR and p-S6K, and reducing the expression of SREBP1 and FASN in BMECs. SIGNIFICANCE: The present study clarified the effect of niacin on milk fat synthesis. The results show that niacin inhibits the synthesis of milk fat in BMECs through the downstream signalling pathway mediated by GPR109A. The function of niacin has been expanded, and knowledge of the new mechanism and signalling pathway will help improve the biosynthesis of milk fat.


Assuntos
Gorduras na Dieta/metabolismo , Células Epiteliais/metabolismo , Glândulas Mamárias Animais/metabolismo , Leite/metabolismo , Niacina/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Animais , Bovinos , Células Epiteliais/efeitos dos fármacos , Feminino , Hipolipemiantes/farmacologia , Glândulas Mamárias Animais/efeitos dos fármacos , Leite/efeitos dos fármacos , Receptores Acoplados a Proteínas G/genética
18.
Nutrients ; 12(8)2020 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-32823541

RESUMO

Obesity is an immunometabolic disease associated with chronic inflammation and the dysregulation of pro- and anti-inflammatory cytokines. One hallmark of obesity is reduced concentrations of the anti-inflammatory adipokine, adiponectin. Pharmacologic doses of niacin produce multiple metabolic benefits, including attenuating high-fat diet (HFD)-induced adipose tissue inflammation and increasing adiponectin concentrations. To determine if adiponectin mediates the anti-inflammatory effects of niacin, male C57BL/6J (WT) and adiponectin null (Adipoq-/-) mice were maintained on a low-fat diet (LFD) or HFD for 6 weeks, before being administered either vehicle or niacin (360 mg/kg/day) for 5 weeks. HFD-fed mice had increased expression of genes associated with macrophage recruitment (Ccl2) and number (Cd68), and increased crown-like structure (CLS) number in adipose tissue. While niacin attenuated Ccl2 expression, there were no effects on Cd68 or CLS number. The absence of adiponectin did not hinder the ability of niacin to reduce Ccl2 expression. HFD feeding increased gene expression of inflammatory markers in the adipose tissue of WT and Adipoq-/- mice. While niacin tended to decrease the expression of inflammatory markers in WT mice, niacin increased their expression in HFD-fed Adipoq-/- mice. Therefore, our results indicate that the absence of adiponectin alters the effects of niacin on markers of adipose tissue inflammation in HFD-fed mice, suggesting that the effects of niacin on tissue cytokines may involve adiponectin.


Assuntos
Adiponectina/deficiência , Tecido Adiposo/metabolismo , Anti-Inflamatórios/farmacologia , Expressão Gênica/efeitos dos fármacos , Niacina/farmacologia , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Quimiocina CCL2/metabolismo , Citocinas/metabolismo , Dieta com Restrição de Gorduras , Dieta Hiperlipídica , Modelos Animais de Doenças , Inflamação , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo
20.
Sci Rep ; 10(1): 12491, 2020 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-32719460

RESUMO

Elevated plasma concentrations of the ketone body ß-hydroxybutyrate (BHB), an endogenous agonist of the hydroxycarboxylic acid receptor 2 (HCA2), is associated with an increased incidence of inflammatory diseases during lactation in dairy cows. In the early stages of this pathology, an increase in neutrophil recruitment is observed; however, the role of BHB remains elusive. This study characterized the effect of BHB and synthetic agonists of the HCA2 receptor on bovine neutrophil chemotaxis and the signaling pathways involved in this process. We demonstrated that treatment with BHB concentrations between 1.2 and 10 mM and two full selective agonists of the HCA2 receptor, MK-1903 and nicotinic acid, increased bovine neutrophil chemotaxis. We also observed that BHB and HCA2 agonists induced calcium release and phosphorylation of AKT, ERK 1/2 and AMPKα. To evaluate the role of these pathways in bovine neutrophil chemotaxis, we used the pharmacological inhibitors BAPTA-AM, pertussis toxin, U73122, LY294002, U0126 and compound C. Our results suggest that these pathways are required for HCA2 agonist-induced bovine neutrophil chemotaxis in non-physiological condition. Concentrations around 1.4 mM of BHB after calving may exert a chemoattractant effect that is key during the onset of the inflammatory process associated with metabolic disorders in dairy cows.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Quimiotaxia , Sistema de Sinalização das MAP Quinases , Neutrófilos/citologia , Neutrófilos/enzimologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Animais , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Bovinos , Quimiotaxia/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Niacina/farmacologia , Fosforilação/efeitos dos fármacos , Pirazóis/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Fosfolipases Tipo C/metabolismo
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