RESUMO
Intestinal transplantation is a complex technical procedure that provides patients suffering from end-stage intestinal failure an opportunity to enjoy improved quality of life, nutrition and survival. Compared to other types of organ transplants, it is a relatively new advancement in the field of organ transplantation. Nevertheless, great advances have been made over the past few decades to the present era, including the use of ischemic preconditioning, gene therapy, and addition of pharmacological supplements to preservation solutions. However, despite these strides, intestinal transplantation is still a challenging endeavor due to several factors. Notable among them is ischemia-reperfusion injury (IRI), which results in loss of cellular integrity and mucosal barrier function. In addition, IRI causes graft failure, delayed graft function, and decreased graft and recipient survival. This has necessitated the search for novel therapeutic avenues and improved transplantation protocols to prevent or attenuate intestinal IRI. Among the many candidate agents that are being investigated to combat IRI and its associated complications, nitric oxide (NO). NO is an endogenously produced gaseous signaling molecule with several therapeutic properties. The purpose of this mini-review is to discuss IRI and its related complications in intestinal transplantation, and NO as an emerging pharmacological tool against this challenging pathological condition. i.
Assuntos
Rejeição de Enxerto , Mucosa Intestinal , Óxido Nítrico , Humanos , Óxido Nítrico/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Rejeição de Enxerto/prevenção & controle , Animais , Intestinos/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/metabolismo , Função da Barreira IntestinalRESUMO
Many pathological processes include nitric oxide (NO), a signaling transduction molecule. Tumors, cardiovascular, cerebrovascular, neurodegenerative, and other illnesses are linked to abnormal NO levels. Thus, evaluating NO levels in vitro and in vivo is crucial for studying chemical biology process of associated disorders. This work devised and manufactured a coumarin-based fluorescent probe ZPS-NO to detect nitric oxide (NO). The reaction between ZPS-NO and NO produced a highly selective and sensitive optical response that caused a powerful fluorescence "turn-on" effect with a ultra-low NO detection limit of 14.5 nM. Furthermore, the probe was applied to sense and image NO in living cells and inflammatory model of zebrafish, as well as to detect NO in periodontitis patients' saliva samples. We anticipate that probe ZPS-NO will serve as a practical and effective tool for assessing the interactions and evaluation of periodontitis development.
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Corantes Fluorescentes , Peixe-Zebra , Animais , Humanos , Corantes Fluorescentes/química , Óxido Nítrico , Saliva , Células HeLa , BiomarcadoresRESUMO
Herein, we describe the rational design, synthesis and in vitro functional characterization of new heme-dependent, direct soluble guanylyl cyclase (sGC) agonists. These new compounds bear a 1H-pyrazolo[3,4-c]pyridin-7(6H)-one skeleton, modified to enable efficient sGC binding and stimulation. To gain insights into structure-activity relationships, the N6-alkylation of the skeleton was explored, while a pyrimidine ring, substituted with various C5'-polar groups, was installed at position C3. Among the newly synthesized 1H-pyrazolo[3,4-c]pyridin-7(6H)-ones, derivatives 14b, 15b and 16a display characteristic features of sGC "stimulators" in A7r5 vascular smooth muscle cells in vitro. They strongly synergize with the NO donor, sodium nitroprusside (SNP) in inducing cGMP generation in a manner that requires the presence of a reduced heme moiety associated with sGC, and elevate the cGMP-responsive phosphorylation of the protein VASP at Ser239. In line with their sGC stimulating capacity, docking calculations of derivatives 16a, 15(a-c) on a cryo-EM structure of human sGC (hsGC) in an ΝΟ-activated state indicated the implication of 1H-pyrazolo[3,4-c]pyridin-7(6H)-one skeleton in efficient bonding interactions with the recently identified region that binds known sGC stimulators, while the presence of either a N6-H or N6-methyl group pointed to enhanced binding affinity. Moreover, the in vitro functional effects of our newly identified sGC stimulators were compatible with a beneficial role in vascular homeostasis. Specifically, derivative 14b reduced A7r5 cell proliferation, while 16a dampened the expression of adhesion molecules ICAM-1 and P/E-Selectin in Human Umbilical Vein Endothelial Cells (HUVECs), as well as the subsequent adhesion of U937 leukocytes to the HUVECs, triggered by tumor necrosis factor alpha (TNF-α) or interleukin-1 beta (IL-1ß). The fact that these compounds elevate cGMP only in the presence of NO may indicate a novel way of interaction with the enzyme and may make them less prone than other direct sGC agonists to induce characteristic hypotension in vivo.
Assuntos
Células Endoteliais , Guanilato Ciclase , Humanos , Células Endoteliais/metabolismo , Ativação Enzimática , Guanilato Ciclase/metabolismo , Heme , Óxido Nítrico/metabolismo , Guanilil Ciclase Solúvel/metabolismo , Vasodilatadores , AlquilaçãoRESUMO
Microglia, resident immune cells in the central nervous system (CNS), play a critical role in maintaining CNS homeostasis. However, microglia activated in response to brain injury produce various inflammatory mediators, including nitric oxide (NO) and proinflammatory cytokines, leading to considerable neuronal damage. NO generated by inducible NO synthase (iNOS) rapidly reacts with superoxide to form a highly toxic product, peroxynitrite. Therefore, iNOS is considered to be a putative therapeutic target for cerebral ischemia. Here, we examined the effects of panobinostat (Pano), a histone deacetylase inhibitor, on lipopolysaccharide (LPS)-induced iNOS expression using rat immortalized microglia HAPI cells. Pano inhibited LPS-induced expression of iNOS mRNA and NO production in a dose-dependent manner; however, it had little effect on the LPS-induced activation of c-Jun N-terminal kinase (JNK) and p38 or nuclear translocation of nuclear factor-κB (NF-κB). The interferon-ß (IFN-ß)/signal transducer and activator of transcription (STAT) pathway is essential for LPS-induced iNOS expression in macrophages/microglia. We also examined the effects of Pano on LPS-induced IFN-ß signaling. Pano markedly inhibited LPS-induced IFN-ß expression and subsequent tyrosine phosphorylation of STAT1. However, the addition of IFN-ß restored the decreased STAT1 phosphorylation but not the decreased iNOS expression. In addition, Pano inhibited the LPS-increased expression of octamer binding protein-2 and interferon regulatory factor 9 responsible for iNOS expression, but IFN-ß addition also failed to restore the decreased expression of these factors. Thus, we conclude that the inhibitory effects of Pano are due not only to the inhibition of the IFN-ß/STAT axis but also to the downregulation of other factors not involved in this axis.
Assuntos
Inibidores de Histona Desacetilases , Lipopolissacarídeos , Microglia , Óxido Nítrico Sintase Tipo II , Óxido Nítrico , Panobinostat , Animais , Microglia/efeitos dos fármacos , Microglia/metabolismo , Lipopolissacarídeos/farmacologia , Óxido Nítrico Sintase Tipo II/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Ratos , Panobinostat/farmacologia , Óxido Nítrico/metabolismo , NF-kappa B/metabolismo , Linhagem Celular , Interferon beta/metabolismo , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
When cultured anaerobically, Enterocloster sp. RD014215 was found to produce 1. Using nuclear magnetic resonance and mass spectroscopy, the planar structure of 1 was determined to be 3-hydroxy-3-(2-oxopropyl)indolin-2-one. The chirality of 1 was implied as S by comparing the optical rotation value of 1 with literature reports of the synthesized compounds. To our knowledge, this work represents the first discovery of the metabolite produced by Enterocloster strain. 1 exhibited inhibition of nitric oxide (NO) production, demonstrating a 50% inhibitory activity (IC50) of 34 µm for NO production by murine macrophage cells subjected to lipopolysaccharide stimulation.
Assuntos
Macrófagos , Óxido Nítrico , Humanos , Camundongos , Animais , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II , Macrófagos/metabolismo , Indóis/farmacologia , Indóis/metabolismo , Lipopolissacarídeos/farmacologiaRESUMO
The objective of this study was to investigate the mechanism underlying LW-1-induced resistance to TMV in wild-type and salicylic acid (SA)-deficient NahG transgenic tobacco plants. Our findings revealed that LW-1 failed to induce antivirus infection activity and increase SA content in NahG tobacco, indicating the crucial role of SA in these processes. Meanwhile, LW-1 triggered defense-related early-signaling nitric oxide (NO) generation, as evidenced by the emergence of NO fluorescence in both types of tobacco upon treatment with LW-1, however, NO fluorescence was stronger in NahG compared to wild-type tobacco. Notably, both of them were eliminated by the NO scavenger cPTIO, which also reversed LW-1-induced antivirus activity and the increase of SA content, suggesting that NO participates in LW-1-induced resistance to TMV, and may act upstream of the SA pathway. Defense-related enzymes and genes were detected in tobacco with or without TMV inoculation, and the results showed that LW-1 regulated both enzyme activity (ß-1,3-glucanase [GLU], catalase [CAT] and phenylalanine ammonia-lyase [PAL]) and gene expression (PR1, PAL, WYKY4) through NO signaling in both SA-dependent and SA-independent pathways.
Assuntos
Resistência à Doença , Nicotiana , Óxido Nítrico , Doenças das Plantas , Ácido Salicílico , Vírus do Mosaico do Tabaco , Nicotiana/metabolismo , Nicotiana/genética , Ácido Salicílico/metabolismo , Ácido Salicílico/farmacologia , Óxido Nítrico/metabolismo , Plantas Geneticamente Modificadas , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Transdução de Sinais , Regulação da Expressão Gênica de Plantas/efeitos dos fármacosRESUMO
Inflammation represents the inherent protective reaction of the human body to various harmful agents and noxious stimuli. Standard anti-inflammatory therapy including nonsteroidal anti-inflammatory drugs are associated with several side effects. In the past decades, people rely on medicinal plants for the treatment of inflammation. The traditional utilization of medicinal plants is regarded as a safe, cost-effective, and broadly accepted approach. In this study, anti-inflammatory activity of plants traditionally utilized by the D'harawal people in Australia has been assessed inâ vitro. Eighty Australian native plants were screened based on the Dharawal Pharmacopeia for their inhibitory effect on the nitric oxide (NO) production in lipopolysaccharides (LPS) and interferon (IFN)-γ stimulated RAW 264.7 murine macrophages for their anti-inflammatory activity. From the eighty ethanolic extracts screened, seventeen displayed potent NO inhibition with an IC50 recorded below 15â µg/mL. The aim of this review was to utilise the ethnopharmacological knowledge and to correlate the anti-inflammatory activity of the seventeen plants with either their known or unknown phytochemicals reported in the literature. In doing so, we have created a snapshot of Australian native plant candidates that warrant further chemical investigation associated with their anti-inflammatory activity.
Assuntos
Anti-Inflamatórios , Lipopolissacarídeos , Óxido Nítrico , Extratos Vegetais , Plantas Medicinais , Camundongos , Austrália , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Animais , Células RAW 264.7 , Plantas Medicinais/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/isolamento & purificação , Humanos , Etnofarmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Interferon gama/metabolismoRESUMO
The disorganized vasculatures in tumors represent a substantial challenge of intratumor nanomedicine delivery to exert the anticancer effects. Herein, we rationally designed a glutathione (GSH)-activated nitric oxide (NO) donor loaded bioinspired lipoprotein system (NO-BLP) to normalize tumor vessels and then promote the delivery efficiency of sequential albumin-bound paclitaxel nanoparticles (PAN) in tumors. NO-BLP exhibited higher tumor accumulation and deeper penetration versus the counterpart liposomal formulation (NO-Lipo) in 4T1 breast cancer tumors, thus producing notable vascular normalization efficacy and causing a 2.33-fold increase of PAN accumulation. The sequential strategy of NO-BLP plus PAN resulted in an 81.03% inhibition of tumor growth in 4T1 tumors, which was better than the NO-BLP monotherapy, PAN monotherapy, and the counterpart NO-Lipo plus PAN treatment. Therefore, the bioinspired lipoprotein of NO-BLP provides an encouraging platform to normalize tumor vessels and promote intratumor delivery of nanomedicines for effective cancer treatment.
Assuntos
Neoplasias da Mama , Nanopartículas , Humanos , Feminino , Paclitaxel Ligado a Albumina/uso terapêutico , Óxido Nítrico , Sistemas de Liberação de Medicamentos/métodos , Paclitaxel , Neoplasias da Mama/tratamento farmacológico , Lipoproteínas/uso terapêutico , Nanopartículas/uso terapêutico , Linhagem Celular TumoralRESUMO
Diabetes mellitus is associated with various complications, mainly caused by the chronic exposure of the cells to high glucose (HG) concentrations. The effects of long-term HG exposure in vitro accompanied by lipopolysaccharide (LPS) application on astrocytes are relatively unknown. We used cell medium with normal (NG, 5.5 mM) or high glucose (HG, 25 mM) for rat astrocyte cultures and measured the release of NO, IL-6, ß-hexosaminidase and cell survival in response to LPS. We first demonstrated that HG long-term incubation of astrocytes increased the release of ß-hexosaminidase without decreasing MTT-detected cell survival, suggesting that there is no cell membrane damage or astrocyte death but could be lysosome exocytosis. Different from what was observed for NG, all LPS concentrations tested at HG resulted in an increase in IL-6, and this was detected for both 6 h and 48 h treatments. Interestingly, ß-hexosaminidase level increased after 48 h of LPS and only at HG. The NO release from astrocytes also increased with LPS application at HG but was less significant. These data endorsed the original hypothesis that long-term hyperglycemia increases proinflammatory activation of astrocytes, and ß-hexosaminidase could be a specific marker of excessive activation of astrocytes associated with exocytosis.
Assuntos
Astrócitos , Interleucina-6 , Animais , Ratos , Lipopolissacarídeos/toxicidade , Acetilglucosaminidase , beta-N-Acetil-Hexosaminidases , Glucose/farmacologiaRESUMO
Fertilizer-intensive agriculture leads to emissions of reactive nitrogen (Nr), posing threats to climate via nitrous oxide (N2O) and to air quality and human health via nitric oxide (NO) and ammonia (NH3) that form ozone and particulate matter (PM) downwind. Adding nitrification inhibitors (NIs) to fertilizers can mitigate N2O and NO emissions but may stimulate NH3 emissions. Quantifying the net effects of these trade-offs requires spatially resolving changes in emissions and associated impacts. We introduce an assessment framework to quantify such trade-off effects. It deploys an agroecosystem model with enhanced capabilities to predict emissions of Nr with or without the use of NIs, and a social cost of greenhouse gas to monetize the impacts of N2O on climate. The framework also incorporates reduced-complexity air quality and health models to monetize associated impacts of NO and NH3 emissions on human health downwind via ozone and PM. Evaluation of our model against available field measurements showed that it captured the direction of emission changes but underestimated reductions in N2O and overestimated increases in NH3 emissions. The model estimated that, averaged over applicable U.S. agricultural soils, NIs could reduce N2O and NO emissions by an average of 11% and 16%, respectively, while stimulating NH3 emissions by 87%. Impacts are largest in regions with moderate soil temperatures and occur mostly within two to three months of N fertilizer and NI application. An alternative estimate of NI-induced emission changes was obtained by multiplying the baseline emissions from the agroecosystem model by the reported relative changes in Nr emissions suggested from a global meta-analysis: -44% for N2O, -24% for NO and +20% for NH3. Monetized assessments indicate that on an annual scale, NI-induced harms from increased NH3 emissions outweigh (8.5-33.8 times) the benefits of reducing NO and N2O emissions in all agricultural regions, according to model-based estimates. Even under meta-analysis-based estimates, NI-induced damages exceed benefits by a factor of 1.1-4. Our study highlights the importance of considering multiple pollutants when assessing NIs, and underscores the need to mitigate NH3 emissions. Further field studies are needed to evaluate the robustness of multi-pollutant assessments.
Assuntos
Agricultura , Fertilizantes , Nitrificação , Óxido Nitroso , Fertilizantes/análise , Óxido Nitroso/análise , Poluentes Atmosféricos/análise , Ozônio/análise , Amônia/análise , Espécies Reativas de Nitrogênio/análise , Nitrogênio/análise , Poluição do Ar/análiseRESUMO
OBJECTIVES: To investigate the antihypertensive effect of crude extract of Chenopodium album (Ca.Cr), based on its medicinal use in hypertension. METHODS: Ca.Cr and its fractions were tested in-vivo in normotensive anesthetized rats for blood pressure-lowering effect. In-vitro experiments were performed on isolated rat aortae to explore the vascular mechanism(s). RESULTS: In normotensive anesthetized rats, Ca.Cr produced a dose-dependent (1-300mg/kg) fall (30%mmHg) in mean arterial pressure (MAP). Among the fractions, nHexane was the most potent (46% fall). In rat aortic rings precontracted with phenylephrine (PE), Ca.Cr and its fractions (except Ca.Aq) produced endothelium-dependent vasorelaxation, which was partially reversed with endothelium removal and by pretreating intact aortic rings with L-NAME (10µM) and atropine (1µM). This relaxation to Ca.Cr and fractions (nHexane, ethylacetate and chloroform) was also eliminated with indomethacin pretreatment, however, it unmasked a vasoconstriction effect with Ca.Cr only. Surprisingly, the aqueous fraction produced a calcium sensitive strong vasoconstriction instead of vasorelaxation. The crude extract and its fractions (except Ca.Aq) also antagonized vasoconstriction induced with high K+ (80mM), suggesting calcium antagonistic effect. The aqueous fraction produced mild vasorelaxation against high K+. This effect was further confirmed when pretreatment of the aortic rings with different concentrations of crude extract and fractions suppressed CaCl2 concentration response curves, similar to verapamil. In acute toxicity test, Ca.Cr extract was found safe up to 5g/kg body weight in mice. CONCLUSION: These findings suggest that crude extract and fractions of C. album produced vasorelaxant effect through muscarinic receptors linked-NO pathway, prostaglandin (endothelium-dependent) and calcium antagonism (endothelium-independent), which explains the blood pressure lowering effect of C. album in rats.
Assuntos
Chenopodium album , Vasodilatação , Ratos , Animais , Camundongos , Pressão Sanguínea , Chenopodium album/metabolismo , Cálcio/metabolismo , Cálcio/farmacologia , Extratos Vegetais/farmacologia , Ratos Sprague-Dawley , Vasodilatadores/farmacologia , Bloqueadores dos Canais de Cálcio , Endotélio/metabolismo , Endotélio Vascular/metabolismoRESUMO
Synthesis of green ammonia (NH3 ) via electrolysis of nitric oxide (NO) is extraordinarily sustainable, but multielectron/proton-involved hydrogenation steps as well as low concentrations of NO can lead to poor activities and selectivities of electrocatalysts. Herein, it is reported that oxygen-defective TiO2 nanoarray supported on Ti plate (TiO2- x /TP) behaves as an efficient catalyst for NO reduction to NH3 . In 0.2 m phosphate-buffered electrolyte, such TiO2- x /TP shows competitive electrocatalytic NH3 synthesis activity with a maximum NH3 yield of 1233.2 µg h-1 cm-2 and Faradaic efficiency of 92.5%. Density functional theory calculations further thermodynamically faster NO deoxygenation and protonation processes on TiO2- x (101) compared to perfect TiO2 (101). And the low energy barrier of 0.7 eV on TiO2- x (101) for the potential-determining step further highlights the greatly improved intrinsic activity. In addition, a Zn-NO battery is fabricated with TiO2- x /TP and Zn plate to obtain an NH3 yield of 241.7 µg h-1 cm-2 while providing a peak power density of 0.84 mW cm-2 .
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Arachis hypogea L. protein fraction-2 (AHP-F2) from the Peanut shell was extracted and characterized and its potent immunomodulatory and anti-leishmanial role was determined in this present study. AHP-F2 was found to be a glycoprotein as the presence of carbohydrates were confirmed by the analysis of high-performance liquid chromatography (HPLC) yielded glucose, galactose, mannose, and xylose. AHP-F2 molecular mass was found to be â¼28 kDa as indicated in MALDI-TOF and peptide mass fingerprinting analysis followed by Mascot search. The peptide matches revealed the similarity of the mannose/glucose binding lectin with 71.07% in the BLAST analysis. After that, the 3D structure of the AHP-F2 model was designed and validated by the Ramachandran plot. The immunomodulatory role of AHP-F2 was established in murine peritoneal macrophages as induction of nitric oxide (NO), and stimulation of proinflammatory cytokines (IL-12 and IFN-γ) in a dose-dependent manner was observed. Interestingly, it was also found that AHP-F2 has interacted with the innate immune receptor, toll-like receptors (TLRs) as established in molecular docking as well as mRNA expression. The anti-leishmanial potential of AHP-F2 was revealed with a prominent inhibition of amastigote growth within the murine macrophages with prompt induction of nitrite release. Altogether, the isolated AHP-F2 from Arachis hypogea L. has strong immunomodulatory and anti-leishmanial potential which may disclose a new path to treat leishmaniasis.
Assuntos
Arachis , Leishmania donovani , Animais , Camundongos , Manose , Ativação de Macrófagos , Simulação de Acoplamento Molecular , Glicoproteínas , Glucose , Leishmania donovani/metabolismo , Óxido Nítrico/metabolismo , Camundongos Endogâmicos BALB CRESUMO
Dimethylarginine dimethylaminohydrolase-1 (DDAH1) expression is frequently elevated in different cancers including prostate cancer (PCa) and enhances nitric oxide (NO) production in tumor cells by metabolising endogenous nitric oxide synthase (NOS) inhibitors. DDAH1 protects the PCa cells from cell death and promotes survival. In this study, we have investigated the cytoprotective role of DDAH1 and determined the mechanism of DDAH1 in protecting the cells in tumor microenvironment. Proteomic analysis of PCa cells with stable overexpression of DDAH1 has identified that oxidative stress-related activity is altered. Oxidative stress promotes cancer cell proliferation, survival and causes chemoresistance. A known inducer of oxidative stress, tert-Butyl Hydroperoxide (tBHP) treatment to PCa cells led to elevated DDAH1 level that is actively involved in protecting the PCa cells from oxidative stress induced cell damage. In PC3-DDAH1- cells, tBHP treatment led to higher mROS levels indicating that the loss of DDAH1 increases the oxidative stress and eventually leads to cell death. Under oxidative stress, nuclear Nrf2 controlled by SIRT1 positively regulates DDAH1 expression in PC3 cells. In PC3-DDAH1+ cells, tBHP induced DNA damage is well tolerated compared to wild-type cells while PC3-DDAH1- became sensitive to tBHP. In PC3 cells, tBHPexposure has increased the production of NO and GSH which may be acting as an antioxidant defence to overcome oxidative stress. Furthermore, in tBHP treated PCa cells, DDAH1 is controlling the expression of Bcl2, active PARP and caspase 3. Taken together, these results confirm that DDAH1 is involved in the antioxidant defence system and promotes cell survival.
Assuntos
Amidoidrolases , Óxido Nítrico , Estresse Oxidativo , Transdução de Sinais , Humanos , Masculino , Amidoidrolases/biossíntese , Amidoidrolases/metabolismo , Antioxidantes/metabolismo , Apoptose , Arginina/metabolismo , Óxido Nítrico/metabolismo , Proteômica , Espécies Reativas de Oxigênio , terc-Butil Hidroperóxido/farmacologia , Neoplasias da Próstata/metabolismo , Células Tumorais CultivadasRESUMO
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by behavioral deficits such as abnormalities in communication, social interaction, anxiety, and repetitive behavior. We have recently shown that the Shank3 mutation in mice representing a model of ASD causes excessive nitric oxide (NO) levels and aberrant protein S-nitrosylation. Further, 10-day daily injections of 7-NI, a neuronal nitric oxide synthase inhibitor, into Shank3Δ4-22 and Cntnap2(-/-) mutant mice (models of ASD) at a dose of 80 mg/kg reversed the manifestations of ASD phenotype. In this study, we proposed an extended release of 7-NI using a novel drug system. Importantly, unlike the intraperitoneal injections, our new preparation of poly (sebacic acid-co-ricinoleic acid) (PSARA) gel containing 7-NI was injected subcutaneously into the mutant mice only once. The animals underwent behavioral testing starting from day 3 post-injection. It should be noted that the developed PSARA gel formulation allowed a slow release of 7-NI maintaining the plasma level of the drug at â¼45 µg/ml/day. Further, we observed improved memory and social interaction and reduced anxiety-like behavior in Shank3 mutant mice. This was accompanied by a reduction in 3-nitrotyrosine levels (an indicator of nitrative/nitrosative stress) in plasma. Overall, we suggest that our single-dose formulation of PSARA gel is very efficient in rendering a therapeutic effect of 7-NI for at least 10 days. This approach may provide in the future a rational design of an effective ASD treatment using 7-NI and its clinical translation.
Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Camundongos , Animais , Transtorno Autístico/genética , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Indazóis , Comportamento Animal , Modelos Animais de Doenças , Proteínas dos Microfilamentos , Proteínas do Tecido NervosoRESUMO
The severe acute respiratory coronavirus 2 (SARS-CoV-2) infection demonstrates a highly variable and unpredictable course. Several reports have claimed a smoker's paradox in coronavirus disease 2019 (COVID-19), in line with previous suggestions that smoking is associated with better survival after acute myocardial infarction and appears protective in preeclampsia. Several plausible physiological explanations exist accounting for the paradoxical observation of smoking engendering protection against SARS-CoV-2 infection. In this review, we delineate novel mechanisms whereby smoking habits and smokers' genetic polymorphism status affecting various nitric oxide (NO) pathways (endothelial NO synthase, cytochrome P450 (CYP450), erythropoietin receptor (EPOR); ß-common receptor (ßcR)), along with tobacco smoke modulation of microRNA-155 and aryl-hydrocarbon receptor (AHR) effects, may be important determinators of SARS-CoV-2 infection and COVID-19 course. While transient NO bioavailability increase and beneficial immunoregulatory modulations through the above-mentioned pathways using exogenous, endogenous, genetic and/or therapeutic modalities may have direct and specific, viricidal SARS-CoV-2 effects, employing tobacco smoke inhalation to achieve protection equals self-harm. Tobacco smoking remains the leading cause of death, illness, and impoverishment.
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Newly synthesized dehydroxymethyl epoxyquinomycin (DHMEQ) derivatives 6-9, which contain a tertiary hydroxyl group instead of the original secondary hydroxyl group, showed improved solubility in alcohol while maintaining their inhibitory activity against nitric oxide (NO) production, which is used as an indicator of nuclear factor-kappa B (NF-κB) inhibitory activity. We also synthesized a derivative 5 having a cyclopropane ring and a tertiary hydroxyl group and examined its inhibitory activity against NO production. Although it reacted with a nucleophile in a flask, it did not inhibit NO production. The change from a secondary hydroxyl group to a tertiary hydroxyl group contributed to improve the solubility of the compounds while retaining NO inhibitory activity, but had no effect on improving the activity of the cyclopropane form. Compounds in which the secondary hydroxyl group of DHMEQ was converted to a tertiary hydroxyl group would be excellent NF-κB inhibitor candidates because their solubility is improved without decreasing NO inhibitory activity.
Assuntos
Ciclopropanos , NF-kappa B , Cicloexanonas/farmacologiaRESUMO
This study aimed to design and synthesize active hybrids of ß-elemene and nitric oxide (NO) donor pharmacophore as potential agents for treating leukemia. Derivatives reported herein exerted better inhibitory effects against human chronic myeloid leukemia K562 cells compared to ß-elemene (IC50 > 100 µM). The most potent compound 18f showed an IC50 value of 0.53 µM against K562 cells, as well as a high NO release level in vitro. In the K562 xenograft tumor mice model, compound 18f effectively inhibited the growth of the tumor, with a significant inhibition rate of 73.18%. After treatment with compound 18f, the body weight of mice did not decrease, indicating that it possessed good safety profile. All these proved that compound 18f was an excellent potential agent against leukemia.
Assuntos
Antineoplásicos , Leucemia , Sesquiterpenos , Humanos , Animais , Camundongos , Doadores de Óxido Nítrico/farmacologia , Doadores de Óxido Nítrico/uso terapêutico , Sesquiterpenos/farmacologia , Sesquiterpenos/uso terapêutico , Células K562 , Leucemia/tratamento farmacológico , Proliferação de Células , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Óxido Nítrico , ApoptoseRESUMO
Nitric oxide (NO) is involved in the pathogenesis of cerebral ischemic injury. Here, we investigated the effects of aging on NO production during cerebral ischemia-reperfusion (IR). Male Wister rats (WRs) were assigned to 12-month-old (older; n = 5) and 3-month-old (younger; n = 7) groups. Similarly, male spontaneous hypertensive rats (SHRs) were allocated to 12-month-old (older; n = 6) and 3-month-old (younger; n = 8) groups. After anesthesia, their NO production was monitored using in vivo microdialysis probes inserted into the left striatum and hippocampus. Forebrain cerebral IR injuries were produced via ligation of the bilateral common carotid arteries, followed by reperfusion. The change in the NO3- of the older rats in the SHR groups in the striatum was less compared to that of the younger rats before ischemia, during ischemia, and after reperfusion (p < 0.05). In the hippocampus, the change in the NO3- of the older rats in the SHR groups was lower compared to that of the younger rats after reperfusion (p < 0.05). There were no significant differences between the two WR groups. Our findings suggested that aging in SHRs affected NO production, especially in the striatum, before and during cerebral ischemia, and after reperfusion. Hypertension and aging may be important factors impacting NO production in brain IR injury.
Assuntos
Lesões Encefálicas , Traumatismo por Reperfusão , Masculino , Ratos , Animais , Ratos Wistar , Óxido Nítrico , Microdiálise , Infarto Cerebral , Ratos Endogâmicos SHR , Reperfusão , Envelhecimento , ProsencéfaloRESUMO
Various studies have revealed that several cancer cell types can upregulate inducible nitric oxide synthase (iNOS) and iNOS-derived nitric oxide (NO) after moderate photodynamic treatment (PDT) sensitized by 5-aminolevulinic acid (ALA)-induced protoporphyrin-IX. As will be discussed, the NO signaled cell resistance to photokilling as well as greater growth and migratory aggressiveness of surviving cells. On this basis, it was predicted that diffusible NO from PDT-targeted cells in a tumor might enhance the growth, migration, and invasiveness of non- or poorly PDT-targeted bystander cells. This was tested using a novel approach in which ALA-PDT-targeted cancer cells on a culture dish were initially segregated from non-targeted bystander cells of the same type via impermeable silicone-rimmed rings. Several hours after LED irradiation, the rings were removed, and both cell populations were analyzed in the dark for various responses. After a moderate extent of targeted cell killing (~25%), bystander proliferation and migration were evaluated, and both were found to be significantly enhanced. Enhancement correlated with iNOS/NO upregulation in surviving PDT-targeted cancer cells in the following cell type order: PC3 > MDA-MB-231 > U87 > BLM. If occurring in an actual PDT-challenged tumor, such bystander effects might compromise treatment efficacy by stimulating tumor growth and/or metastatic dissemination. Mitigation of these and other negative NO effects using pharmacologic adjuvants that either inhibit iNOS transcription or enzymatic activity will be discussed.