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1.
J Extracell Vesicles ; 11(7): e12242, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35790086

RESUMO

Eukaryotic cells, including cancer cells, secrete highly heterogeneous populations of extracellular vesicles (EVs). EVs could have different subcellular origin, composition and functional properties, but tools to distinguish between EV subtypes are scarce. Here, we tagged CD63- or CD9-positive EVs secreted by triple negative breast cancer cells with Nanoluciferase enzyme, to set-up a miniaturized method to quantify secretion of these two EV subtypes directly in the supernatant of cells. We performed a cell-based high-content screening to identify clinically-approved drugs able to affect EV secretion. One of the identified hits is Homosalate, an anti-inflammatory drug found in sunscreens which robustly increased EVs' release. Comparing EVs induced by Homosalate with those induced by Bafilomycin A1, we demonstrate that: (1) the two drugs act on EVs generated in distinct subcellular compartments, and (2) EVs released by Homosalate-, but not by Bafilomycin A1-treated cells enhance resistance to anchorage loss in another recipient epithelial tumour cell line. In conclusion, we identified a new drug modifying EV release and demonstrated that under influence of different drugs, triple negative breast cancer cells release EV subpopulations from different subcellular origins harbouring distinct functional properties.


Assuntos
Vesículas Extracelulares , Neoplasias de Mama Triplo Negativas , Suplementos Nutricionais , Humanos , Salicilatos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
2.
PLoS One ; 17(7): e0269983, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35776756

RESUMO

Tetramethrin (Tm) is a commonly used pesticide that has been reported to exert estrogen-antagonistic effects selectively on female rats. The present study was undertaken to assess the protective role of lobaric acid (La) on estrous cycle in Tm-treated female Wistar rats. Female rats were exposed to Tm (50 mg/kg b.w/day) only or in combination with La at low (50 mg/kg b.w/day) or high (100 mg/kg b.w/day) dose for 30 days. The results showed that Tm altered the estrous cycle of female rats by decreasing the levels of luteinizing hormone, follicular-stimulating hormone, progesterone, estrone, and estradiol while increasing testosterone level. The morphology of vaginal smears of Tm-treated female rats showed the presence of abnormal cells and/or structures at different phases of estrus cycle. Strikingly, in (Tm + La)-treated rats, all the observed adverse effects of Tm on the hormonal parameters, cell morphology, and the length of each phase of estrous cycle were significantly diminished in a dose-dependent manner. The docking results showed that La competes with Tm for Gonadotropin-Releasing Hormone (GnRH) receptor, thereby reducing the toxicity of Tm but did not cancel the response of GnRH receptor completely. In conclusion, our results designated that La could be used as a potential candidate in the management of insecticide-induced alterations of the reproductive cycle of rodents.


Assuntos
Ciclo Estral , Salicilatos , Animais , Depsídeos , Ciclo Estral/fisiologia , Feminino , Lactonas , Piretrinas , Ratos , Ratos Wistar , Salicilatos/farmacologia
3.
Molecules ; 27(15)2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35897943

RESUMO

SiO2-SO3H, with a surface area of 115 m2/g and pore volume of 0.38 cm3g-1, and 1.32 mmol H+/g was used as a 20% w/w catalyst for the preparation of methyl salicylate (wintergreen oil or MS) from acetylsalicylic acid (ASA). A 94% conversion was achieved in a microwave reactor over 40 min at 120 °C in MeOH. The resulting crude product was purified by flash chromatography. The catalyst could be reused three times.


Assuntos
Micro-Ondas , Dióxido de Silício , Aspirina , Biocombustíveis , Catálise , Esterificação , Óleos Voláteis , Extratos Vegetais , Óleos Vegetais/química , Salicilatos
4.
J Int Adv Otol ; 18(4): 378-380, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35894537

RESUMO

Ototoxic side effects such as sensorineural hearing loss and tinnitus can be caused by acute salicylate intoxication. Bilateral symmetric sensori- neural hearing loss involving all tested frequencies is a typical pattern of hearing loss in acute salicylate intoxication, which usually resolves within 2 or 3 days without any specific treatment for ototoxicity. Herein, we report a case of suicidal aspirin intoxication resulting in sudden bilateral hearing loss and vertigo. The patient exhibited spontaneous downbeat nystagmus, and the mechanism underlying this characteristic nystagmus is discussed.


Assuntos
Perda Auditiva Neurossensorial , Perda Auditiva Súbita , Nistagmo Patológico , Aspirina , Perda Auditiva Bilateral/induzido quimicamente , Perda Auditiva Neurossensorial/etiologia , Perda Auditiva Súbita/etiologia , Humanos , Nistagmo Patológico/induzido quimicamente , Salicilatos , Ideação Suicida
5.
Phys Chem Chem Phys ; 24(28): 17068-17076, 2022 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-35791920

RESUMO

While common molecular anions show a strong propensity to undergo electron detachment upon UV excitation, this process often occurs in competition with molecular ion dissociation. The factors that affect the balance between these two major possible decay pathways have not been well understood to date. Laser photodissociation spectroscopy of the deprotonated forms of the UV filter molecules, Homosalate (HS) and Octyl Salicylate (OS), i.e. [HS - H]- and [OS - H]-, was used to acquire gas-phase UV absorption spectra for [HS - H]- and [OS - H]-via photodepletion from 3.0-5.8 eV. No photofragmentation (i.e. dissociation of the ionic molecular framework) was observed for either [HS - H]- and [OS - H]- following photoexcitation, revealing that electron loss entirely dominates the electronic decay pathways for these systems. High-level quantum chemical calculations were used to map out the excited states associated with [HS - H]- and [OS - H]-, revealing that the minimum-energy crossing points (MECPs) between the S1 and S0 states are located in elevated regions of the potential energy surface, making internal conversion unlikely. These results are consistent with our experimental observation that electron detachment out-competes hot ground state molecular fragmentation. More generally, our results reveal that the competition between molecular dissociation and electron detachment following anion photoexcitation can be determined by the magnitude of the energy gap between the excitation energy and the MECPs, rather than being a simple function of whether the excitation energy lies above the anion's vertical detachment energy.


Assuntos
Elétrons , Salicilatos , Ânions/química , Íons/química
6.
Oxid Med Cell Longev ; 2022: 8002566, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35707278

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a refractory chronic respiratory disease with progressively exacerbating symptoms and a high mortality rate. There are currently only two effective drugs for IPF; thus, there is an urgent need to develop new therapeutics. Previous experiments have shown that ginkgolic acid (GA), as a SUMO-1 inhibitor, exerted an inhibitory effect on cardiac fibrosis induced by myocardial infarction. Regarding the pathogenesis of PF, previous studies have concluded that small ubiquitin-like modifier (SUMO) polypeptides bind multiple target proteins and participate in fibrosis of multiple organs, including PF. In this study, we found altered expression of SUMO family members in lung tissues from IPF patients. GA mediated the reduced expression of SUMO1/2/3 and the overexpression of SENP1 in a PF mouse model, which improved PF phenotypes. At the same time, the protective effect of GA on PF was also confirmed in the SENP1-KO transgenic mice model. Subsequent experiments showed that SUMOylation of SMAD4 was involved in PF. It was inhibited by TGF-ß1, but GA could reverse the effects of TGF-ß1. SENP1 also inhibited the SUMOylation of SMAD4 and then participated in epithelial-mesenchymal transition (EMT) downstream of TGF-ß1. We also found that SENP1 regulation of SMAD4 SUMOylation affected reactive oxygen species (ROS) production during TGF-ß1-induced EMT and that GA prevented this oxidative stress through SENP1. Therefore, GA may inhibit the SUMOylation of SMAD4 through SENP1 and participate in TGF-ß1-mediated pulmonary EMT, all of which reduce the degree of PF. This study provided potential novel targets and a new alternative for the future clinical testing in PF.


Assuntos
Bleomicina , Fibrose Pulmonar Idiopática , Animais , Bleomicina/toxicidade , Transição Epitelial-Mesenquimal , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/tratamento farmacológico , Camundongos , Salicilatos , Proteína Smad4/genética , Proteína Smad4/metabolismo , Proteína Smad4/farmacologia , Sumoilação , Fator de Crescimento Transformador beta1/metabolismo
7.
Molecules ; 27(12)2022 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-35745076

RESUMO

Poplar bark and leaves can be an attractive source of salicylates and other biologically active compounds used in medicine. However, the biochemical variability of poplar material requires a standardization prior to processing. The official analytical protocols used in the pharmaceutical industry rely on the extraction of active compounds, which makes their determination long and costly. An analysis of plant materials in their native state can be performed using vibrational spectroscopy. This paper presents for the first time a comparison of diffuse reflectance in the near- and mid-infrared regions, attenuated total reflection, and Raman spectroscopy used for the simultaneous determination of salicylates and flavonoids in poplar bark and leaves. Based on 185 spectra of various poplar species and hybrid powdered samples, partial least squares regression models, characterized by the relative standard errors of prediction in the 4.5-9.9% range for both calibration and validation sets, were developed. These models allow for fast and precise quantification of the studied active compounds in poplar bark and leaves without any chemical sample treatment.


Assuntos
Flavonoides , Salicilatos , Calibragem , Análise dos Mínimos Quadrados , Casca de Planta , Folhas de Planta
8.
Plant Sci ; 320: 111279, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35643618

RESUMO

The survival and adaptation of angiosperms depends on the proper timing of flowering. The weedy species Chenopodium ficifolium serves as a useful diploid model for comparing the transition to flowering with the important tetraploid crop Chenopodium quinoa due to the close phylogenetic relationship. The detailed transcriptomic and hormonomic study of the floral induction was performed in the short-day accession C. ficifolium 459. The plants grew more rapidly under long days but flowered later than under short days. The high levels of abscisic, jasmonic, and salicylic acids at long days were accompanied by the elevated expression of the genes responding to oxidative stress. The increased concentrations of stress-related phytohormones neither inhibited the plant growth nor accelerated flowering in C. ficifolium 459 at long photoperiods. Enhanced content of cytokinins and the stimulation of cytokinin and gibberellic acid signaling pathways under short days may indicate the possible participation of these phytohormones in floral initiation. The accumulation of auxin metabolites suggests the presence of a dynamic regulatory network in C. ficifolium 459.


Assuntos
Chenopodium , Chenopodium/genética , Chenopodium/metabolismo , Citocininas/metabolismo , Regulação da Expressão Gênica de Plantas , Filogenia , Reguladores de Crescimento de Plantas/metabolismo , Salicilatos
9.
J Mol Model ; 28(6): 168, 2022 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-35612680

RESUMO

Dismutation reaction of superoxide radical catalyzed by EUK-134 has lower activation energy than non-catalytic reaction, and therefore, EUK-134 catalyzes dismutation reaction of superoxide radical. For non-catalytic dismutation reaction of hydrogen peroxide, there are three possible reaction paths, among which MEP3 has the lowest activation energy, and therefore, is thought to be the most probable reaction path. Dismutation reaction of hydrogen peroxide catalyzed by EUK-134 occurs in two successive steps and has lower energy barrier than non-catalytic dismutation reaction, and therefore, EUK-134 is thought to catalyze the dismutation reaction of hydrogen peroxide. HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) and ESP-fitted charge analysis of EUK-134 indicate that Mn atom plays an electron acceptor and donor for dismutation reactions of superoxide radical and hydrogen peroxide catalyzed by EUK-134, respectively.


Assuntos
Compostos Organometálicos , Superóxidos , Antioxidantes , Catalase , Peróxido de Hidrogênio , Salicilatos , Superóxido Dismutase
10.
Biosci Rep ; 42(5)2022 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-35506370

RESUMO

The roles of the kynurenine pathway (KP) of tryptophan (Trp) degradation in serotonin deficiency in major depressive disorder (MDD) and the associated inflammatory state are considered in the present study. Using molecular docking in silico, we demonstrate binding of antidepressants to the crystal structure of tryptophan 2,3-dioxygenase (TDO) but not to indoleamine 2,3-dioxygenase (IDO). TDO is inhibited by a wide range of antidepressant drugs. The rapidly acting antidepressant ketamine does not dock to either enzyme but may act by inhibiting kynurenine monooxygenase thereby antagonising glutamatergic activation to normalise serotonin function. Antidepressants with anti-inflammatory properties are unlikely to act by direct inhibition of IDO but may inhibit IDO induction by lowering levels of proinflammatory cytokines in immune-activated patients. Of six anti-inflammatory drugs tested, only salicylate docks strongly to TDO and apart from celecoxib, the other five dock to IDO. TDO inhibition remains the major common property of antidepressants and TDO induction the most likely mechanism of defective serotonin synthesis in MDD. TDO inhibition and increased free Trp availability by salicylate may underpin the antidepressant effect of aspirin and distinguish it from other nonsteroidal anti-inflammatory drugs. The controversial findings with IDO in MDD patients with an inflammatory state can be explained by IDO induction being overridden by changes in subsequent KP enzymes influencing glutamatergic function. The pathophysiology of MDD may be underpinned by the interaction of serotonergic and glutamatergic activities.


Assuntos
Transtorno Depressivo Maior , Triptofano , Anti-Inflamatórios , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Inflamação , Cinurenina/metabolismo , Simulação de Acoplamento Molecular , Salicilatos , Serotonina/metabolismo , Triptofano/metabolismo
12.
Int J Biol Macromol ; 211: 85-93, 2022 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-35561857

RESUMO

The polylactic acid composite films were successfully fabricated via the technique of solvent casting using cellulose acetate (20%, wt) as the reinforcing material and phenyl salicylate as the ultraviolet (UV) absorbent and antibacterial agent. Polylactic acid-cellulose acetate-phenyl salicylate composite films displayed complete absorption effect at the region of UV-C (280-100 nm) and UV-B (315-280 nm), and more than 95% UV absorption effect at the region of UV-A (400-315 nm). These results indicate that the UV shielding performance of the composite films could be significantly improve by addition of phenyl salicylate. Moreover, the addition of 20% phenyl salicylate could improve the steam resistance, mechanical properties and thermal stability of the films, and the composite films had also better antibacterial activity against Escherichia coli. The composite films could reduce the decay rate of fresh lilies and extend their storage time. The degradation characteristics of the films were explored in the natural environment and the laboratory level, which provided application prospect for the development of degradable food packaging materials with anti-ultraviolet and anti-bacteria effect.


Assuntos
Antibacterianos , Celulose , Antibacterianos/farmacologia , Celulose/análogos & derivados , Celulose/farmacologia , Escherichia coli , Embalagem de Alimentos/métodos , Poliésteres , Salicilatos
13.
Eur J Pharmacol ; 926: 175026, 2022 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-35569546

RESUMO

High doses of salicylate induce tinnitus in humans and experimental animals. The Dorsal Cochlear Nucleus is implicated with the genesis of tinnitus, and increased activity in this nucleus is seen in animal models of tinnitus. Incubation of brainstem slices containing the DCN with millimolar salicylate reduces the spontaneous firing of glycinergic cartwheel neurons and glycinergic neurotransmission on fusiform neurons, the principal neuron of this nucleus. However, the mechanism of salicylate mediating this effect is not known. Recently, we have shown that KATP channels strongly modulate the spontaneous firing of cartwheel neurons. We tested if KATP channels could mediate the effects of salicylate on cartwheel neurons. Perfusion of 1.4 mM salicylate hyperpolarizes the membrane of cartwheel neurons and stops firing. Salicylate produces an outward current similar to the KATP current seen in quiet cartwheel neurons. Activation of this current is occluded by the KATP agonist diazoxide, which is produced by the opening of KATP channels. The antagonist of AMP-kinase (AMPK), dorsomorphim, inhibited salicylate effects, suggesting that they could be mediated by activation of this kinase. Still, the AMPK agonist, AICAR, did not reproduce salicylate effects but occluded them. Additionally, inhibiting mitochondrial ATP synthesis with the protonophore CCCP reproduced, albeit with less efficacy, and inhibited the effects of salicylate. We concluded that salicylate in millimolar concentrations opens KATP channels in DCN cartwheel neurons, inhibiting spontaneous firing of these neurons, probably by activating AMPK and reducing mitochondrial ATP synthesis.


Assuntos
Núcleo Coclear , Zumbido , Proteínas Quinases Ativadas por AMP , Trifosfato de Adenosina/farmacologia , Animais , Núcleo Coclear/fisiologia , Canais KATP/farmacologia , Neurônios , Ratos , Salicilatos/farmacologia
14.
Environ Pollut ; 307: 119502, 2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-35605833

RESUMO

Amyl salicylate (AS) is a fragrance massively used as a personal care product and following the discharged in wastewaters may end up in the aquatic environment representing a potential threat for the ecosystem and living organisms. AS was recently detected in water of the Venice Lagoon, a vulnerable area continuously subjected to the income of anthropogenic chemicals. The lagoon is a relevant area for mollusc farming, including the Mediterranean mussels (Mytilus galloprovincialis) having an important economic and ecological role. Despite high levels of AS occurred in water of the Lagoon of Venice, no studies investigated the possible consequences of AS exposures on species inhabiting this ecosystem to date. For the first time, we applied a multidisciplinary approach to investigate the potential effects of the fragrance AS on Mediterranean mussels. To reach such a goal, bioaccumulation, cellular, biochemical, and molecular analyses (RNA-seq and microbiota characterization) were measured in mussels treated for 7 and 14 days with different AS Venice lagoon environmental levels (0.1 and 0.5 µg L-1). Despite chemical investigations suggested low AS bioaccumulation capability, cellular and molecular analyses highlighted the disruption of several key cellular processes after the prolonged exposures to the high AS concentration. Among them, potential immunotoxicity and changes in transcriptional regulation of pathways involved in energy metabolism, stress response, apoptosis and cell death regulations have been observed. Conversely, exposure to the low AS concentration demonstrated weak transcriptional changes and transient increased representation of opportunistic pathogens, as Arcobacter genus and Vibrio aestuarianus. Summarizing, this study provides the first overview on the effects of AS on one of the most widely farmed mollusk species.


Assuntos
Microbiota , Mytilus , Poluentes Químicos da Água , Animais , Mytilus/metabolismo , Odorantes/análise , Salicilatos/toxicidade , Água/metabolismo , Poluentes Químicos da Água/análise
15.
J Diabetes Res ; 2022: 2042273, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35502441

RESUMO

Purpose: Insulin receptor (InsR) sensitizers represent a new type of therapeutic agent for the treatment of diabetes, with 2'-O-methylperlatolic acid (2-O-M) being a potential InsR targeting drug. The purpose of this study was to determine whether 2-O-M functions as an activator of the insulin signaling pathway, regulating glucose hemostasis through the InsR and exerting a glucose-lowering effect in an animal model of diabetes. Methods: SPR-based analyses were used to detect the binding of different concentrations of 2-O-M to the InsR. The protein levels of IR-ß, p-IR, AKT, and p-AKT in Hepa and C2C12 cell lines and liver and muscle tissues were determined by western blotting. Glucose uptake capacity was determined in C2C12 cells. Streptozotocin-induced diabetic mice were randomly divided into four groups: the control, insulin treated, 2-O-M treated, and combined insulin and 2-O-M treated. Mice were injected with 2-O-M or normal saline and the average blood glucose concentration after 120 min, and the serum levels of insulin, glucagon, and C-peptide were measured. Next, qRT-PCR was performed to detect the mRNA expression of genes involved in lipid and glucose metabolism in the liver and muscle tissues. Results: 2-O-M binds to the extracellular domain of the InsR. Moreover, combination treatment with 2-O-M and insulin resulted in significant activation of the insulin signaling pathway in vitro and significant stimulation of the glucose uptake capacity of C2C12 myotubes. In mice with streptozotocin-induced diabetes, 2-O-M significantly prolonged the blood glucose-lowering effect of insulin, significantly reduced the secretion of exogenous insulin, and reduced the blood glucose concentration in vivo. In addition, treatment with 2-O-M alone significantly enhanced the phosphorylation of AKT in muscle tissue, which enhanced glucose uptake in C2C12 myotubes. Further, 2-O-M significantly increased glucagon secretion and enhanced liver gluconeogenesis to prevent hypoglycemia. Conclusion: 2-O-M enhances the hypoglycemic effect of insulin through the insulin signaling pathway and can be used as a complement to insulin. This synergetic effect may lower the required dose of insulin and protect ß cells.


Assuntos
Diabetes Mellitus Experimental , Resistência à Insulina , Animais , Benzoatos , Glicemia , Depsídeos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Glucagon , Glucose/farmacologia , Insulina/metabolismo , Resistência à Insulina/fisiologia , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor de Insulina/metabolismo , Salicilatos , Transdução de Sinais , Estreptozocina/farmacologia
16.
Molecules ; 27(10)2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35630527

RESUMO

It was established that isopropyl salicylate can be used similarly to 1,3-diketones as a key component for a new efficient extraction system for selective separation of alkali metal cations. According to DFT modeling of complexes of isopropyl salicylate and 1,3-diketone with alkali metal cations (Li+, Na+, K+), six-membered metallacycles are formed whose stability decreases along the series Li > Na > K, which results in the observed enhanced affinity to lithium. The extraction ability of isopropyl salicylate is manifested in the presence of trioctylphosphine oxide (TOPO). The newly obtained complexes of isopropyl salicylate with alkali metal cations as well as their extracts in a mixture with TOPO are characterized by means of FT-IR, Raman, and NMR spectroscopy. The probable structure of the extracted lithium complex is presumed and the role of TOPO in the extraction process is investigated in detail. Extraction experiments showed extremely high separation coefficients for Li/Na and Li/K pairs in the extraction from a model multi-component solution.


Assuntos
Lítio , Metais Alcalinos , Cátions , Lítio/química , Metais Alcalinos/química , Compostos Organofosforados , Salicilatos , Sódio/química , Espectroscopia de Infravermelho com Transformada de Fourier
17.
Molecules ; 27(10)2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35630834

RESUMO

The leaves of Gaultheria procumbens are polyphenol-rich traditional medicines used to treat inflammation-related diseases. The present study aimed to optimise the solvent for the effective recovery of active leaf components through simple direct extraction and verify the biological effects of the selected extract in a model of human neutrophils ex vivo. The extracts were comprehensively standardised, and forty-one individual polyphenols, representing salicylates, catechins, procyanidins, phenolic acids, and flavonoids, were identified by UHPLC-PDA-ESI-MS3. The chosen methanol-water (75:25, v/v) extract (ME) was obtained with the highest extraction yield and total phenolic levels (397.9 mg/g extract's dw), including 98.9 mg/g salicylates and 299.0 mg/g non-salicylate polyphenols. In biological tests, ME revealed a significant and dose-dependent ability to modulate pro-oxidant and pro-inflammatory functions of human neutrophils: it strongly reduced the ROS level and downregulated the release of pro-inflammatory cytokines and tissue remodelling enzymes, especially IL-1ß and elastase 2, in cells stimulated by fMLP, LPS, or fMLP + cytochalasin B. The extracts were also potent direct scavengers of in vivo relevant oxidants (O2•-, •OH, and H2O2) and inhibitors of pro-inflammatory enzymes (cyclooxygenase-2, hyaluronidase, and lipoxygenase). The statistically significant correlations between the tested variables revealed the synergic contribution of individual polyphenols to the observed effects and indicated them as useful active markers for the standardisation of the extract/plant material. Moreover, the safety of ME was confirmed in cytotoxicity tests. The obtained results might partially explain the ethnomedicinal application of G. procumbens leaves and support the usage of the standardised leaf extract in the adjuvant treatment of oxidative stress and inflammation-related chronic diseases.


Assuntos
Gaultheria , Humanos , Peróxido de Hidrogênio/farmacologia , Inflamação/tratamento farmacológico , Neutrófilos , Oxidantes/farmacologia , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Espécies Reativas de Oxigênio/farmacologia , Salicilatos/farmacologia
18.
Nat Commun ; 13(1): 1984, 2022 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-35418171

RESUMO

Structure determination of pharmaceutical compounds is invaluable for drug development but remains challenging for those that form as small crystals with defects. Bismuth subsalicylate, among the most commercially significant bismuth compounds, is an active ingredient in over-the-counter medications such as Pepto-Bismol, used to treat dyspepsia and H. pylori infections. Despite its century-long history, the structure of bismuth subsalicylate is still under debate. Here we show that advanced electron microscopy techniques, namely three-dimensional electron diffraction and scanning transmission electron microscopy, can give insight into the structure of active pharmaceutical ingredients that are difficult to characterize using conventional methods due to their small size or intricate structural features. Hierarchical clustering analysis of three-dimensional electron diffraction data from ordered crystals of bismuth subsalicylate revealed a layered structure. A detailed investigation using high-resolution scanning transmission electron microscopy showed variations in the stacking of layers, the presence of which has likely hindered structure solution by other means. Together, these modern electron crystallography techniques provide a toolbox for structure determination of active pharmaceutical ingredients and drug discovery, demonstrated by this study of bismuth subsalicylate.


Assuntos
Infecções por Helicobacter , Compostos Organometálicos , Bismuto , Infecções por Helicobacter/tratamento farmacológico , Humanos , Preparações Farmacêuticas , Salicilatos
19.
Int J Mol Sci ; 23(7)2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35409287

RESUMO

Ginkgolic acid (C13:0) (GA), isolated from Ginkgo biloba, is a potential therapeutic agent for type 2 diabetes. A series of GA analogs were designed and synthesized for the evaluation of their structure-activity relationship with respect to their antidiabetic effects. Unlike GA, the synthetic analog 1e exhibited improved inhibitory activity against PTPN9 and significantly stimulated glucose uptake via AMPK phosphorylation in differentiated 3T3-L1 adipocytes and C2C12 myotubes; it also induced insulin-dependent AKT activation in C2C12 myotubes in a concentration-dependent manner. Docking simulation results showed that 1e had a better binding affinity through a unique hydrophobic interaction with a PTPN9 hydrophobic groove. Moreover, 1e ameliorated palmitate-induced insulin resistance in C2C12 cells. This study showed that 1e increases glucose uptake and suppresses palmitate-induced insulin resistance in C2C12 myotubes via PTPN9 inhibition; thus, it is a promising therapeutic candidate for treating type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Humanos , Insulina/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Palmitatos/metabolismo , Salicilatos , Transdução de Sinais , Relação Estrutura-Atividade
20.
Am J Physiol Heart Circ Physiol ; 322(5): H880-H889, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35363580

RESUMO

Reactive oxygen species (ROS)-mediated reductions in nitric oxide (NO)-dependent dilation are evident in adults with major depressive disorder (MDD); however, the upstream mechanisms remain unclear. Here, we hypothesized that nuclear factor-κB (NF-κB) activation-induced ROS production contributes to microvascular endothelial dysfunction in MDD. Thirteen treatment-naive adults with MDD (6 women; 19-23 yr) and 10 healthy nondepressed adults (HAs; 5 women; 20-25 yr) were tested before and after (open-label design) systemic NF-κB knockdown (nonacetylated salicylate; 3,000-4,500 mg/day × 4 days). Red cell flux (laser Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine (ACh), alone and in combination with NO synthase inhibition [NG-nitro-l-arginine methyl ester (l-NAME)] or ROS scavenging (apocynin). Serum salicylate concentrations following treatment were not different between groups (22.8 ± 7.4 HAs vs. 20.8 ± 4.3 mg/dL MDD; P = 0.46). When compared with HAs, the NO-dependent component of ACh-induced dilation was blunted in adults with MDD before (P = 0.023), but not after (P = 0.27), salsalate treatment. In adults with MDD, the magnitude of improvement in endothelium-dependent dilation following salsalate treatment was inversely related to the degree of functional impairment at baseline (R2 = 0.43; P = 0.025). Localized ROS scavenging improved NO-dependent dilation before (P < 0.01), but not after (P > 0.05), salsalate treatment. Salsalate did not alter systemic concentrations of pro- or anti-inflammatory cytokines (all P > 0.05). These data suggest that NF-κB activation, via increased vascular ROS production, contributes to blunted NO-dependent dilation in young adults with MDD but otherwise free of clinical disease. These data provide the first direct evidence for a mechanistic role of vascular inflammation-associated endothelial dysfunction in human depression.NEW & NOTEWORTHY Our data indicate that short-term treatment with therapeutic doses of the nuclear factor-κB (NF-κB) inhibitor salsalate improved nitric oxide (NO)-mediated endothelium-dependent dilation in adults with major depressive disorder (MDD). In adults with MDD, acute localized scavenging of reactive oxygen species (ROS) with apocynin improved NO-dependent dilation before, but not after, salsalate administration. These data suggest that activation of NF-κB, in part via stimulation of vascular ROS production, contributes to blunted NO-mediated endothelium-dependent dilation in young adults with MDD.


Assuntos
Transtorno Depressivo Maior , Acetilcolina/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Dilatação , Endotélio Vascular , Feminino , Humanos , Masculino , NF-kappa B , Óxido Nítrico , Espécies Reativas de Oxigênio , Salicilatos/farmacologia , Salicilatos/uso terapêutico , Vasodilatação , Adulto Jovem
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