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2.
Pestic Biochem Physiol ; 200: 105806, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38582572

RESUMO

Boscalid, a widely used SDHI fungicide, has been employed in plant disease control for over two decades. However, there is currently no available information regarding its antifungal activity against Sclerotium rolfsii and the potential risk of resistance development in this pathogen. In this study, we evaluated the sensitivity of 100 S. rolfsii strains collected from five different regions in China during 2018-2019 to boscalid using mycelial growth inhibition method and assessed the risk of resistance development. The EC50 values for boscalid ranged from 0.2994 µg/mL to 1.0766 µg/mL against the tested strains, with an average EC50 value of 0.7052 ± 0.1473 µg/mL. Notably, a single peak sensitivity baseline was curved, indicating the absence of any detected resistant strains. Furtherly, 10 randomly selected strains of S. rolfsii were subjected to chemical taming to evaluate its resistance risk to boscalid, resulting in the successful generation of six stable and inheritable resistant mutants. These mutants exhibited significantly reduced mycelial growth, sclerotia production, and virulence compared to their respective parental strains. Cross-resistance tests revealed a correlation between boscalid and flutolanil, benzovindiflupyr, pydiflumetofen, fluindapyr, and thifluzamide; however, no cross-resistance was observed between boscalid and azoxystrobin. Thus, we conclude that the development risk of resistance in S. rolfsii to boscalid is low. Boscalid can be used as an alternative fungicide for controlling peanut sclerotium blight when combined with other fungicides that have different mechanisms of action. Finally, the target genes SDHB, SDHC, and SDHD in S. rolfsii were initially identified, cloned and sequenced to elucidate the mechanism of S. rolfsii resistance to boscalid. Two mutation genotypes were found in the mutants: SDHD-D111H and SDHD-H121Y. The mutants carrying SDHD-H121Y exhibited moderate resistance, while the mutants with SDHD-D111H showed low resistance. These findings contribute to our comprehensive understanding of molecular mechanisms underlying plant pathogens resistance to SDHI fungicides.


Assuntos
Basidiomycota , Compostos de Bifenilo , Fungicidas Industriais , Niacinamida/análogos & derivados , Fungicidas Industriais/farmacologia , Succinato Desidrogenase , Medição de Risco , Doenças das Plantas/microbiologia
3.
Alzheimers Res Ther ; 16(1): 71, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38576025

RESUMO

BACKGROUND: The aggregation and spread of misfolded amyloid structured proteins, such as tau and α-synuclein, are key pathological features associated with neurodegenerative disorders, including Alzheimer's and Parkinson's disease. These proteins possess a prion-like property, enabling their transmission from cell to cell leading to propagation throughout the central and peripheral nervous systems. While the mechanisms underlying their intracellular spread are still being elucidated, targeting the extracellular space has emerged as a potential therapeutic approach. The glymphatic system, a brain-wide pathway responsible for clearing extracellular metabolic waste from the central nervous system, has gained attention as a promising target for removing these toxic proteins. METHODS: In this study, we investigated the impact of long-term modulation of glymphatic function on tau aggregation and spread by chronically treating a mouse model of tau propagation with a pharmacological inhibitor of AQP4, TGN-020. Thy1-hTau.P301S mice were intracerebrally inoculated with tau into the hippocampus and overlying cortex, and subsequently treated with TGN-020 (3 doses/week, 50 mg/kg TGN-020, i.p.) for 10-weeks. During this time, animal memory was studied using cognitive behavioural tasks, and structural MR images were acquired of the brain in vivo prior to brain extraction for immunohistochemical characterisation. RESULTS: Our findings demonstrate increased tau aggregation in the brain and transhemispheric propagation in the hippocampus following the inhibition of glymphatic clearance. Moreover, disruption of the glymphatic system aggravated recognition memory in tau inoculated mice and exacerbated regional changes in brain volume detected in the model. When initiation of drug treatment was delayed for several weeks post-inoculation, the alterations were attenuated. CONCLUSIONS: These results indicate that by modulating AQP4 function and, consequently, glymphatic clearance, it is possible to modify the propagation and pathological impact of tau in the brain, particularly during the initial stages of the disease. These findings highlight the critical role of the glymphatic system in preserving healthy brain homeostasis and offer valuable insights into the therapeutic implications of targeting this system for managing neurodegenerative diseases characterized by protein aggregation and spread.


Assuntos
Doença de Alzheimer , Sistema Glinfático , Niacinamida/análogos & derivados , Tiadiazóis , Camundongos , Animais , Doença de Alzheimer/patologia , Encéfalo/metabolismo , Sistema Glinfático/metabolismo , Proteínas tau/metabolismo
4.
Environ Pollut ; 347: 123685, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38460591

RESUMO

Boscalid (2-Chloro-N-(4'-chlorobiphenyl-2-yl) nicotinamide), a pyridine carboxamide fungicide, is an inhibitor of the complex II of the respiration chain in fungal mitochondria. As boscalid is only moderately toxic for aquatic organisms (LC50 > 1-10 mg/L), current environmental levels of this compound in aquatic ecosystems, in the range of ng/L-µg/L, are considered safe for aquatic organisms. In this study, we have exposed zebrafish (Danio rerio), Japanese medaka (Oryzias latipes) and Daphnia magna to a range of concentrations of boscalid (1-1000 µg/L) for 24 h, and the effects on heart rate (HR), basal locomotor activity (BLA), visual motor response (VMR), startle response (SR), and habituation (HB) to a series of vibrational or light stimuli have been evaluated. Moreover, changes in the profile of the main neurotransmitters have been determined. Boscalid altered HR in a concentration-dependent manner, leading to a positive or negative chronotropic effect in fish and D. magna, respectively. While boscalid decreased BLA and increased VMR in Daphnia, these behaviors were not altered in fish. For SR and HB, the response was more species- and concentration-specific, with Daphnia exhibiting the highest sensitivity. At the neurotransmission level, boscalid exposure decreased the levels of L-aspartic acid in fish larvae and increased the levels of dopaminergic metabolites in D. magna. Our study demonstrates that exposure to environmental levels of boscalid alters cardiac activity, impairs ecologically relevant behaviors, and leads to changes in different neurotransmitter systems in phylogenetically distinct vertebrate and invertebrate models. Thus, the results presented emphasize the need to review the current regulation of this fungicide.


Assuntos
Compostos de Bifenilo , Fungicidas Industriais , Niacinamida/análogos & derivados , Poluentes Químicos da Água , Animais , Fungicidas Industriais/metabolismo , Ecossistema , Organismos Aquáticos , Peixe-Zebra/metabolismo , Daphnia , Niacinamida/toxicidade , Poluentes Químicos da Água/metabolismo
5.
Physiol Behav ; 278: 114521, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38492911

RESUMO

Epilepsy is a neurological condition distinguished by recurrent and unexpected seizures. Astrocytic channels and transporters are essential for maintaining normal neuronal functionality. The astrocytic water channel, aquaporin-4 (AQP4), which plays a pivotal role in regulating water homeostasis, is a potential target for epileptogenesis. In present study, we examined the effect of different doses (10, 50, 100 µM and 5 mM) of AQP4 inhibitor, 2-nicotinamide-1, 3, 4-thiadiazole (TGN-020), during kindling acquisition, on seizure parameters and seizure-induced cognitive impairments. Animals were kindled by injection of pentylenetetrazole (PTZ: 37.5 mg/kg, i.p.). TGN-020 was administered into the right lateral cerebral ventricle 30 min before PTZ every alternate day. Seizure parameters were assessed 20 min after PTZ administration. One day following the last PTZ injection, memory performance was investigated using spontaneous alternation in Y-maze and novel object recognition (NOR) tests. The inhibition of AQP4 during the kindling process significantly decreased the maximal seizure stage and seizure duration (two-way ANOVA, P = 0.0001) and increased the latency of seizure onset and the number of PTZ injections required to induce different seizure stages (one-way ANOVA, P = 0.0001). Compared to kindled rats, the results of the NOR tests showed that AQP4 inhibition during PTZ-kindling prevented recognition memory impairment. Based on these results, AQP4 could be involved in seizure development and seizure-induced cognitive impairment. More investigation is required to fully understand the complex interactions between seizure activity, water homeostasis, and cognitive dysfunction, which may help identify potential therapeutic targets for these conditions.


Assuntos
Disfunção Cognitiva , Excitação Neurológica , Niacinamida/análogos & derivados , Tiadiazóis , Ratos , Animais , Pentilenotetrazol/toxicidade , Convulsões/induzido quimicamente , Convulsões/complicações , Convulsões/tratamento farmacológico , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Água/efeitos adversos
6.
Commun Biol ; 7(1): 255, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38429435

RESUMO

Nicotinamide phosphoribosyltransferase (NAMPT) plays an important role in the biosynthesis of nicotinamide adenine dinucleotide (NAD+) via the nicotinamide (NAM) salvage pathway. While the structural biochemistry of eukaryote NAMPT has been well studied, the catalysis mechanism of prokaryote NAMPT at the molecular level remains largely unclear. Here, we demonstrated the NAMPT-mediated salvage pathway is functional in the Gram-negative phytopathogenic bacterium Xanthomonas campestris pv. campestris (Xcc) for the synthesis of NAD+, and the enzyme activity of NAMPT in this bacterium is significantly higher than that of human NAMPT in vitro. Our structural analyses of Xcc NAMPT, both in isolation and in complex with either the substrate NAM or the product nicotinamide mononucleotide (NMN), uncovered significant details of substrate recognition. Specifically, we revealed the presence of a NAM binding tunnel that connects the active site, and this tunnel is essential for both catalysis and inhibitor binding. We further demonstrated that NAM binding in the tunnel has a positive cooperative effect with NAM binding in the catalytic site. Additionally, we discovered that phosphorylation of the His residue at position 229 enhances the substrate binding affinity of Xcc NAMPT and is important for its catalytic activity. This work reveals the importance of NAMPT in bacterial NAD+ synthesis and provides insights into the substrate recognition and the catalytic mechanism of bacterial type II phosphoribosyltransferases.


Assuntos
Niacinamida , Xanthomonas campestris , Humanos , Niacinamida/metabolismo , NAD/metabolismo , Mononucleotídeo de Nicotinamida/metabolismo , Mononucleotídeo de Nicotinamida/farmacologia , Xanthomonas campestris/metabolismo , Nicotinamida Fosforribosiltransferase/química , Nicotinamida Fosforribosiltransferase/metabolismo , Fosforilação
7.
PeerJ ; 12: e17056, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38436036

RESUMO

Balance involves several sensory modalities including vision, proprioception and the vestibular system. This study aims to investigate vestibulospinal activation elicited by tone burst stimulation in various muscles and how head position influences these responses. We recorded electromyogram (EMG) responses in different muscles (sternocleidomastoid-SCM, cervical erector spinae-ES-C, lumbar erector spinae-ES-L, gastrocnemius-G, and tibialis anterior-TA) of healthy participants using tone burst stimulation applied to the vestibular system. We also evaluated how head position affected the responses. Tone burst stimulation elicited reproducible vestibulospinal reflexes in the SCM and ES-C muscles, while responses in the distal muscles (ES-L, G, and TA) were less consistent among participants. The magnitude and polarity of the responses were influenced by the head position relative to the cervical spine. When the head was rotated or tilted, the polarity of the vestibulospinal responses changed, indicating the integration of vestibular and proprioceptive inputs in generating these reflexes. Overall, our study provides valuable insights into the complexity of vestibulospinal reflexes and their modulation by head position. However, the high variability in responses in some muscles limits their clinical application. These findings may have implications for future research in understanding vestibular function and its role in posture and movement control.


Assuntos
Orientação Espacial , Vestíbulo do Labirinto , Humanos , Percepção Espacial , Vértebras Cervicais , Cafeína , Músculos do Pescoço , Niacinamida
8.
Acta Neuropathol Commun ; 12(1): 37, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38429841

RESUMO

Leber's hereditary optic neuropathy (LHON) is driven by mtDNA mutations affecting Complex I presenting as progressive retinal ganglion cell dysfunction usually in the absence of extra-ophthalmic symptoms. There are no long-term neuroprotective agents for LHON. Oral nicotinamide provides a robust neuroprotective effect against mitochondrial and metabolic dysfunction in other retinal injuries. We explored the potential for nicotinamide to protect mitochondria in LHON by modelling the disease in mice through intravitreal injection of the Complex I inhibitor rotenone. Using MitoV mice expressing a mitochondrial-tagged YFP in retinal ganglion cells we assessed mitochondrial morphology through super-resolution imaging and digital reconstruction. Rotenone induced Complex I inhibition resulted in retinal ganglion cell wide mitochondrial loss and fragmentation. This was prevented by oral nicotinamide treatment. Mitochondrial ultrastructure was quantified by transition electron microscopy, demonstrating a loss of cristae density following rotenone injection, which was also prevented by nicotinamide treatment. These results demonstrate that nicotinamide protects mitochondria during Complex I dysfunction. Nicotinamide has the potential to be a useful treatment strategy for LHON to limit retinal ganglion cell degeneration.


Assuntos
Atrofia Óptica Hereditária de Leber , Rotenona , Camundongos , Animais , Rotenona/toxicidade , Rotenona/metabolismo , Niacinamida/efeitos adversos , Niacinamida/metabolismo , Mitocôndrias/metabolismo , Células Ganglionares da Retina , Atrofia Óptica Hereditária de Leber/genética , Atrofia Óptica Hereditária de Leber/metabolismo , Atrofia Óptica Hereditária de Leber/terapia , Complexo I de Transporte de Elétrons/metabolismo
9.
Methods Cell Biol ; 185: 165-195, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38556447

RESUMO

The mucosal surface of gastrointestinal tract is lined with epithelial cells that establish an effective barrier between the lumen and internal environment through intercellular junctions, preventing the passage of potentially harmful substances. The "intestinal barrier function" consist of a defensive system that prevent the passage of antigens, toxins, and microbial products, while maintains the correct development of the epithelial barrier, the immune system and the acquisition of tolerance toward dietary antigens and intestinal microbiota. Intestinal morphology changes subsequent to nutritional variations, stress, aging or diseases, which can also affect the composition of the microbiota, altering the homeostasis of the intestine. A growing body of evidence suggests that alterations in intestinal barrier function favor the development of exaggerated immune responses, leading to metabolic endotoxemia, which seems to be the origin of many chronic metabolic diseases such as type 2 diabetes mellitus (T2DM). Although the mechanisms are still unknown, the interaction between dietary patterns, gut microbiota, intestinal mucosa, and metabolic inflammation seems to be a key factor for the development of T2DM, among other diseases. This chapter details the different techniques that allow evaluating the morphological and molecular alterations that lead of the intestinal barrier dysfunction in a T2DM experimental model. To induce both diabetic metabolic disturbances and gut barrier disruption, Wistar rats were fed a high-saturated fat and high-cholesterol diet and received a single dose of streptozotocin/nicotinamide. This animal model may contribute to clarify the understanding of the role of intestinal barrier dysfunction on the late-stage T2DM etiology.


Assuntos
Diabetes Mellitus Tipo 2 , Ratos , Animais , Diabetes Mellitus Tipo 2/metabolismo , Estreptozocina/metabolismo , Niacinamida/farmacologia , Niacinamida/metabolismo , Ratos Wistar , Mucosa Intestinal/metabolismo , Colesterol/metabolismo
10.
JASA Express Lett ; 4(3)2024 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-38426890

RESUMO

English-speaking bimodal and bilateral cochlear implant (CI) users can segregate competing speech using talker sex cues but not spatial cues. While tonal language experience allows for greater utilization of talker sex cues for listeners with normal hearing, tonal language benefits remain unclear for CI users. The present study assessed the ability of Mandarin-speaking bilateral and bimodal CI users to recognize target sentences amidst speech maskers that varied in terms of spatial cues and/or talker sex cues, relative to the target. Different from English-speaking CI users, Mandarin-speaking CI users exhibited greater utilization of spatial cues, particularly in bimodal listening.


Assuntos
Implantes Cocleares , Percepção da Fala , Humanos , Fala , Sinais (Psicologia) , Idioma , Cafeína , Niacinamida
11.
Transl Vis Sci Technol ; 13(3): 24, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38546981

RESUMO

Purpose: To investigate the potential effects and mechanism of nicotinamide riboside (NR) on the oxidative stress and fibrosis model of human trabecular meshwork (HTM) cell line cells. Methods: HTM cells were pretreated with NR, followed by the induction of oxidative injury and fibrosis by hydrogen peroxide (H2O2) and TGF-ß2, respectively. Cell viability was tested using Hoechst staining and MTT assays, cell proliferation was assessed by EdU assay, and cell apoptosis was detected by flow cytometry and western blotting. DCFH-DA and DHE probes were used to measure the level of reactive oxygen species (ROS), and MitoTracker staining was used to measure the mitochondrial membrane potential (MMP). Fibrotic responses, including cell migration and deposition of extracellular matrix (ECM) proteins, were detected via Transwell assays, qRT-PCR, and immunoblotting. Results: NR pretreatment improved the viability, proliferation, and MMP of H2O2-treated HTM cells. Compared to cells treated solely with H2O2, HTM cells treated with both NR and H2O2, exhibited a reduced rate of apoptosis and generation of ROS. Compared with H2O2 pretreatment, NR pretreatment upregulated expression of the JAK2/Stat3 pathway but inhibited mitogen-activated protein kinase (MAPK) pathway expression. Moreover, 10-ng/mL TGF-ß2 promoted cell proliferation and migration, which were inhibited by NR pretreatment. Both qRT-PCR and immunoblotting showed that NR inhibited the expression of fibronectin in a TGF-ß2-induced fibrosis model. Conclusions: NR has a protective effect on oxidative stress and fibrosis in HTM cells, which may be related to the JAK2/Stat3 pathway and MAPK pathway. Translational Relevance: Our research provides the ongoing data for potential therapy of NAD+ precursors in glaucoma.


Assuntos
Niacinamida/análogos & derivados , Compostos de Piridínio , Malha Trabecular , Fator de Crescimento Transformador beta2 , Humanos , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/farmacologia , Fator de Crescimento Transformador beta2/metabolismo , Fator de Crescimento Transformador beta2/farmacologia , Malha Trabecular/metabolismo , Malha Trabecular/patologia , Peróxido de Hidrogênio/farmacologia , Peróxido de Hidrogênio/metabolismo , Estresse Oxidativo/fisiologia , Fibrose
12.
J Med Chem ; 67(6): 4463-4482, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38471014

RESUMO

Sorafenib, a multiple kinase inhibitor, is widely used as a first-line treatment for hepatocellular carcinoma. However, there is a need for more effective alternatives when sorafenib proves insufficient. In this study, we aimed to design a structure that surpasses sorafenib's efficacy, leading us to synthesize sorafenib-ruthenium complexes for the first time and investigate their properties. Our results indicate that the sorafenib-ruthenium complexes exhibit superior epidermal growth factor receptor (EGFR) inhibition compared to sorafenib alone. Interestingly, among these complexes, Ru3S demonstrated high activity against various cancer cell lines including sorafenib-resistant HepG2 cells while exhibiting significantly lower cytotoxicity than sorafenib in healthy cell lines. Further evaluation of cell cycle, cell apoptosis, and antiangiogenic effects, molecular docking, and molecular dynamics studies revealed that Ru3S holds great potential as a drug candidate. Additionally, when free Ru3S was encapsulated into polymeric micelles M1, enhanced cytotoxicity on HepG2 cells was observed. Collectively, these findings position Ru3S as a promising candidate for EGFR inhibition and warrant further exploration for drug development purposes.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Rutênio , Humanos , Sorafenibe/farmacologia , Rutênio/farmacologia , Simulação de Acoplamento Molecular , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Niacinamida/farmacologia , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Receptores ErbB/metabolismo , Apoptose , Sistemas de Liberação de Medicamentos , Proliferação de Células
13.
Biochem Biophys Res Commun ; 708: 149778, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38507867

RESUMO

The increasing prevalence of lean diabetes has prompted the generation of animal models that mimic metabolic disease in humans. This study aimed to determine the optimum streptozotocin-nicotinamide (STZ-NA) dosage ratio to elicit lean diabetic features in a rat model. It also used a proton nuclear magnetic resonance (1H NMR) urinary metabolomics approach to identify the metabolic effect of metformin treatment on this novel rat model. Three different STZ-NA dosage regimens (by body weight: Group A: 110 mg/kg NA and 45 mg/kg STZ; Group B: 180 mg/kg NA and 65 mg/kg STZ and Group C: 120 mg/kg NA and 60 mg/kg STZ) were administered to Sprague-Dawley rats along with oral metformin. Group A diabetic rats (A-DC) showed favorable serum biochemical analyses and a more positive response toward oral metformin administration relative to the other STZ-NA dosage ratio groups. Orthogonal partial least squares-discriminant analysis (OPLS-DA) revealed that glucose, citrate, pyruvate, hippurate, and methylnicotinamide differentiating the OPLS-DA of A-MTF rats (Group A diabetic rats treated with metformin) and A-DC model rats. Subsequent metabolic pathway analyses revealed that metformin treatment was associated with improvement in dysfunctions caused by STZ-NA induction, including carbohydrate metabolism, cofactor metabolism, and vitamin and amino acid metabolism. In conclusion, our results identify the best STZ-NA dosage ratio for a rat model to exhibit lean type 2 diabetic features with optimum sensitivity to metformin treatment. The data presented here could be informative to improve our understanding of non-obese diabetes in humans through the identification of possible activated metabolic pathways in the STZ-NA-induced diabetic rats model.


Assuntos
Diabetes Mellitus Experimental , Metformina , Humanos , Ratos , Animais , Metformina/uso terapêutico , Metformina/farmacologia , Niacinamida/efeitos adversos , Estreptozocina , Diabetes Mellitus Experimental/metabolismo , Ratos Sprague-Dawley , Espectroscopia de Prótons por Ressonância Magnética , Metabolômica/métodos , Espectroscopia de Ressonância Magnética , Hipoglicemiantes/farmacologia , Glicemia/análise
14.
J Nucl Med ; 65(4): 560-565, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38453363

RESUMO

In metastatic castration-resistant prostate cancer (mCRPC) patients treated with prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), the recently proposed criteria for evaluating response to PSMA PET (RECIP 1.0) based on 68Ga- and 18F-labeled PET agents provided prognostic information in addition to changes in prostate-specific antigen (PSA) levels. Our aim was to evaluate the prognostic performance of this framework for overall survival (OS) in patients undergoing RLT and imaged with [18F]PSMA-1007 PET/CT and compare the prognostic performance with the PSA-based response assessment. Methods: In total, 73 patients with mCRPC who were scanned with [18F]PSMA-1007 PET/CT before and after 2 cycles of RLT were retrospectively analyzed. We calculated the changes in serum PSA levels (ΔPSA) and quantitative PET parameters for the whole-body tumor burden (SUVmean, SUVmax, PSMA tumor volume, and total lesion PSMA). Men were also classified following the Prostate Cancer Working Group 3 (PCWG3) criteria for ΔPSA and RECIP 1.0 for PET imaging response. We performed univariable Cox regression analysis, followed by multivariable and Kaplan-Meier analyses. Results: Median OS was 15 mo with a median follow-up time of 14 mo. Univariable Cox regression analysis provided significant associations with OS for ΔPSA (per percentage, hazard ratio [HR], 1.004; 95% CI, 1.002-1.007; P < 0.001) and PSMA tumor volume (per unit, HR, 1.003; 95% CI, 1.000-1.005; P = 0.03). Multivariable Cox regression analysis confirmed ΔPSA (per percentage, HR, 1.004; 95% CI, 1.001-1.006; P = 0.006) as an independent prognosticator for OS. Kaplan-Meier analyses provided significant segregation between individuals with versus those without any PSA response (19 mo vs. 14 mo; HR, 2.00; 95% CI, 0.95-4.18; P = 0.04). Differentiation between patients with or without progressive disease (PD) was also feasible when applying PSA-based PCWG3 (19 mo vs. 9 mo for non-PD and PD, respectively; HR, 2.29; 95% CI, 1.03-5.09; P = 0.01) but slightly failed when applying RECIP 1.0 (P = 0.08). A combination of both response systems (PCWG3 and RECIP 1.0), however, yielded the best discrimination between individuals without versus those with PD (19 mo vs. 8 mo; HR, 2.78; 95% CI, 1.32-5.86; P = 0.002). Conclusion: In patients with mCRPC treated with RLT and imaged with [18F]PSMA-1007, frameworks integrating both the biochemical (PCWG3) and PET-based response (RECIP 1.0) may best assist in identifying subjects prone to disease progression.


Assuntos
Niacinamida , Oligopeptídeos , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração , Ureia , Humanos , Masculino , Dipeptídeos/efeitos adversos , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Lutécio , Niacinamida/análogos & derivados , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Prognóstico , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/radioterapia , Estudos Retrospectivos , Resultado do Tratamento , Ureia/análogos & derivados
15.
Cells ; 13(5)2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38474420

RESUMO

NAD+ boosting via nicotinamide riboside (NR) confers anti-inflammatory effects. However, its underlying mechanisms and therapeutic potential remain incompletely defined. Here, we showed that NR increased the expression of CC-chemokine receptor 7 (CCR7) in human M1 macrophages by flow cytometric analysis of cell surface receptors. Consequently, chemokine ligand 19 (CCL19, ligand for CCR7)-induced macrophage migration was enhanced following NR administration. Metabolomics analysis revealed that prostaglandin E2 (PGE2) was increased by NR in human monocytes and in human serum following in vivo NR supplementation. Furthermore, NR-mediated upregulation of macrophage migration through CCL19/CCR7 was dependent on PGE2 synthesis. We also demonstrated that NR upregulated PGE2 synthesis through SIRT3-dependent post-transcriptional regulation of cyclooxygenase 2 (COX-2). The NR/SIRT3/migration axis was further validated using the scratch-test model where NR and SIRT3 promoted more robust migration across a uniformly disrupted macrophage monolayer. Thus, NR-mediated metabolic regulation of macrophage migration and wound healing may have therapeutic potential for the topical management of chronic wound healing.


Assuntos
Dinoprostona , Niacinamida/análogos & derivados , Compostos de Piridínio , Sirtuína 3 , Humanos , Dinoprostona/metabolismo , Ligantes , Receptores CCR7/metabolismo , Macrófagos/metabolismo
16.
Int J Mol Sci ; 25(5)2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38474253

RESUMO

The brain's unique characteristics make it exceptionally susceptible to oxidative stress, which arises from an imbalance between reactive oxygen species (ROS) production, reactive nitrogen species (RNS) production, and antioxidant defense mechanisms. This review explores the factors contributing to the brain's vascular tone's vulnerability in the presence of oxidative damage, which can be of clinical interest in critically ill patients or those presenting acute brain injuries. The brain's high metabolic rate and inefficient electron transport chain in mitochondria lead to significant ROS generation. Moreover, non-replicating neuronal cells and low repair capacity increase susceptibility to oxidative insult. ROS can influence cerebral vascular tone and permeability, potentially impacting cerebral autoregulation. Different ROS species, including superoxide and hydrogen peroxide, exhibit vasodilatory or vasoconstrictive effects on cerebral blood vessels. RNS, particularly NO and peroxynitrite, also exert vasoactive effects. This review further investigates the neuroprotective effects of antioxidants, including superoxide dismutase (SOD), vitamin C, vitamin E, and the glutathione redox system. Various studies suggest that these antioxidants could be used as adjunct therapies to protect the cerebral vascular tone under conditions of high oxidative stress. Nevertheless, more extensive research is required to comprehensively grasp the relationship between oxidative stress and cerebrovascular tone, and explore the potential benefits of antioxidants as adjunctive therapies in critical illnesses and acute brain injuries.


Assuntos
Lesões Encefálicas , Oxigênio , Humanos , Espécies Reativas de Oxigênio/metabolismo , Oxigênio/farmacologia , Nitrogênio/farmacologia , Estresse Oxidativo , Antioxidantes/farmacologia , Espécies Reativas de Nitrogênio/metabolismo , Niacinamida/farmacologia , Lesões Encefálicas/tratamento farmacológico
17.
Proc Natl Acad Sci U S A ; 121(11): e2313594121, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38442182

RESUMO

The specific roles that different types of neurons play in recovery from injury is poorly understood. Here, we show that increasing the excitability of ipsilaterally projecting, excitatory V2a neurons using designer receptors exclusively activated by designer drugs (DREADDs) restores rhythmic bursting activity to a previously paralyzed diaphragm within hours, days, or weeks following a C2 hemisection injury. Further, decreasing the excitability of V2a neurons impairs tonic diaphragm activity after injury as well as activation of inspiratory activity by chemosensory stimulation, but does not impact breathing at rest in healthy animals. By examining the patterns of muscle activity produced by modulating the excitability of V2a neurons, we provide evidence that V2a neurons supply tonic drive to phrenic circuits rather than increase rhythmic inspiratory drive at the level of the brainstem. Our results demonstrate that the V2a class of neurons contribute to recovery of respiratory function following injury. We propose that altering V2a excitability is a potential strategy to prevent respiratory motor failure and promote recovery of breathing following spinal cord injury.


Assuntos
Diafragma , Traumatismos da Medula Espinal , Animais , Camundongos , Tronco Encefálico , Cafeína , Neurônios , Niacinamida
18.
Drug Des Devel Ther ; 18: 829-843, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38524877

RESUMO

Tyrosine kinase inhibitors (TKIs) have been recognized as crucial agents for treating various tumors, and one of their key targets is the intracellular site of the vascular endothelial growth factor receptor (VEGFR). While TKIs have demonstrated their effectiveness in solid tumor patients and increased life expectancy, they can also lead to adverse cardiovascular effects including hypertension, thromboembolism, cardiac ischemia, and left ventricular dysfunction. Among the TKIs, sorafenib was the first approved agent and it exerts anti-tumor effects on hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) by inhibiting angiogenesis and tumor cell proliferation through targeting VEGFR and RAF. Unfortunately, the adverse cardiovascular effects caused by sorafenib not only affect solid tumor patients but also limit its application in curing other diseases. This review explores the mechanisms underlying sorafenib-induced cardiovascular adverse effects, including endothelial dysfunction, mitochondrial dysfunction, endoplasmic reticulum stress, dysregulated autophagy, and ferroptosis. It also discusses potential treatment strategies, such as antioxidants and renin-angiotensin system inhibitors, and highlights the association between sorafenib-induced hypertension and treatment efficacy in cancer patients. Furthermore, emerging research suggests a link between sorafenib-induced glycolysis, drug resistance, and cardiovascular toxicity, necessitating further investigation. Overall, understanding these mechanisms is crucial for optimizing sorafenib therapy and minimizing cardiovascular risks in cancer patients.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Hipertensão , Neoplasias Renais , Neoplasias Hepáticas , Humanos , Sorafenibe/efeitos adversos , Carcinoma Hepatocelular/patologia , Antineoplásicos/efeitos adversos , Fator A de Crescimento do Endotélio Vascular , Niacinamida , Compostos de Fenilureia/efeitos adversos , Neoplasias Hepáticas/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Hipertensão/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos
19.
J Agric Food Chem ; 72(12): 6702-6710, 2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38484107

RESUMO

The discovery of novel and easily accessible antifungal compounds is an imperative issue in agrochemical innovation. Our continuing research with the o-aminophenyloxazoline (NHPhOx) scaffold demonstrated the viability of introducing phenylacetamides for identifying novel antifungal leads. An antifungal function-oriented molecular evaluation was conducted for the previously identified lead R-LE008. Fine-tuning of the α-position and scaffold hopping of acid segment and NHPhOx enables α-oximido-arylacetamide as a novel antifungal model. The concomitant function-oriented diversification produces a panel of antifungal leads CN19, CN21b, CN28, and CN31 against Sclerotinia sclerotiorum and Botrytis cinerea. The crucial and multidimensional effect of the configuration of the acquired amides on the antifungal performance is demonstrated specifically by the separable CN21 isomers. The Z-isomer (CN21b), with an EC50 value of 0.97 µM against B. cinerea, is significantly more potent than its E-isomer (CN21a) and the positive control boscalid. More importantly, compound CN21b can efficiently inhibit resistant B. cinerea strains. CN21b demonstrates a better in vivo preventative effect (82.1%) than those of CN21a (48.1%) and boscalid (55.1%) at 100 µM. CN21b showed a distinct binding model from those of the boscalid and CN21a in the molecular docking simulation. A further morphological investigation by scanning electron microscopy revealed the different mycelia shrinkage of B. cinerea treated by CN21 isomers. The easy accessibility and cost-effectiveness demonstrated the practical potential of α-oximido-phenylacetamide containing NHPhOx as a new model for agrochemical innovation.


Assuntos
Antifúngicos , Compostos de Bifenilo , Fungicidas Industriais , Niacinamida/análogos & derivados , Antifúngicos/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular , Botrytis , Agroquímicos/farmacologia , Fungicidas Industriais/química
20.
Pharmazie ; 79(1): 6-10, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38509628

RESUMO

Promoting antidiabetic phytomedicines necessitates evidence-based preclinical investigations, particularly in animal models. The present study investigated the validity of using the streptozotocin-nicotinamide-induced type 2 diabetic (STZ/NA-induced T2DM) model to evaluate the effects of Physalis peruviana leaf crude extracts on controlling blood glucose levels and regulating physiological biomarkers in rats. Aqueous and methanol extracts dissolved in carboxymethylcellulose 1% (100, 200, mg/kg/day) were administered orally to STZ/NA-induced T2DM rats alongside glibenclamide (5 mg/kg) as the standard drug for four weeks. Blood samples were collected in fasting rats on days 1, 7, 14, 21, and 28 to measure glucose concentration, lipoprotein-cholesterol, and common serum biomarkers. Nutrition characteristics were also monitored, as well as the pancreas histology. Administration of STZ/NA in Wistar rats induced the T2DM significantly lower than did STZ alone (glycaemia 200 vs 400 mg/dL). The significant effects observed with plant extracts compared to untreated diabetic rats were blood glucose reduction (28-52 %), HDL-C increase, LDL-C decrease, ALAT increase, WBC increase, body weight gain (24%), and pancreas protection. The findings confirm the antidiabetic effect of P. peruviana in T2DM animal model.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Physalis , Ratos , Animais , Glicemia , Niacinamida/efeitos adversos , Ratos Wistar , Estreptozocina/efeitos adversos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Extratos Vegetais , Folhas de Planta , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Biomarcadores
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