RESUMEN
The need of pharmacological strategies to preclude breast cancer development motivated us to develop a non-aqueous microemulsion (ME) capable of forming a depot after administration in the mammary tissue and uptake of interstitial fluids for prolonged release of the retinoid fenretinide. The selected ME was composed of phosphatidylcholine/tricaprylin/propylene glycol (45:5:50, w/w/w) and presented a droplet diameter of 175.3 ± 8.9 nm. Upon water uptake, the ME transformed successively into a lamellar phase, gel, and a lamellar phase-containing emulsion in vitro as the water content increased and released 30% of fenretinide in vitro after 9 days. Consistent with the slow release, the ME formed a depot in cell cultures and increased fenretinide IC50 values by 68.3- and 13.2-fold in MCF-7 and T-47D cells compared to a solution, respectively. At non-cytotoxic concentrations, the ME reduced T-47D cell migration by 75.9% and spheroid growth, resulting in â¼30% smaller structures. The depot formed in vivo prolonged a fluorochrome release for 30 days without producing any sings of local irritation. In a preclinical model of chemically induced carcinogenesis, ME administration every 3 weeks for 3 months significantly reduced (4.7-fold) the incidence of breast tumors and increased type II collagen expression, which might contribute to limit spreading. These promising results support the potential ME applicability as a preventive therapy of breast cancer.
Asunto(s)
Anticarcinógenos/administración & dosificación , Neoplasias de la Mama/prevención & control , Fenretinida/administración & dosificación , Neoplasias Mamarias Experimentales/prevención & control , Animales , Anticarcinógenos/farmacocinética , Neoplasias de la Mama/inducido químicamente , Neoplasias de la Mama/patología , Supervivencia Celular/efectos de los fármacos , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinética , Liberación de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Emulsiones , Femenino , Fenretinida/farmacocinética , Humanos , Concentración 50 Inhibidora , Células MCF-7 , Glándulas Mamarias Animales/efectos de los fármacos , Glándulas Mamarias Animales/patología , Neoplasias Mamarias Experimentales/inducido químicamente , Neoplasias Mamarias Experimentales/patología , Metilnitrosourea/administración & dosificación , Metilnitrosourea/toxicidad , Ratones , RatasRESUMEN
Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic inflammatory disease without consistently effective treatment. We investigate the role of toll-like receptor 4 (TLR4) on voiding dysfunction and inflammation in the cyclophosphamide (CYP)-induced mouse cystitis. Male C57BL/6 [wild-type, (WT)] and/or TLR4 knockout (TLR4-/-) mice were treated with an injection of CYP (300 mg/kg, 24 h) or saline (10 ml/kg). The pharmacological blockade of the TLR4 by resatorvid (10 mg/kg) was also performed 1 h prior CYP-injection in WT mice. Urodynamic profiles were assessed by voiding stain on filter paper and filling cystometry. Contractile responses to carbachol were measured in isolated bladders. In CYP-exposed WT mice, mRNA for TLR4, myeloid differentiation primary response 88, and TIR-domain-containing adapter-inducing interferon-ß increased by 45%, 72%, and 38%, respectively ( P < 0.05). In free-moving mice, CYP-exposed mice exhibited a higher number of urinary spots and smaller urinary volumes. Increases of micturition frequency and nonvoiding contractions, concomitant with decreases of intercontraction intervals and capacity, were observed in the filling cystometry of WT mice ( P < 0.05). Carbachol-induced bladder contractions were significantly reduced in the CYP group, which was paralleled by reduced mRNA for M2 and M3 muscarinic receptors. These functional and molecular alterations induced by CYP were prevented in TLR4-/- and resatorvid-treated mice. Additionally, the increased levels of inflammatory markers induced by CYP exposure, myeloperoxidase activity, interleukin-6, and tumor necrosis factor-alpha were significantly reduced by resatorvid treatment. Our findings reveal a central role for the TLR4 signaling pathway in initiating CYP-induced bladder dysfunction and inflammation and thus emphasize that TLR4 receptor blockade may have clinical value for IC/BPS treatment.
Asunto(s)
Antiinflamatorios/farmacología , Ciclofosfamida , Cistitis Intersticial/prevención & control , Sulfonamidas/farmacología , Receptor Toll-Like 4/antagonistas & inhibidores , Receptor Toll-Like 4/deficiencia , Vejiga Urinaria/efectos de los fármacos , Proteínas Adaptadoras del Transporte Vesicular/genética , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Animales , Cistitis Intersticial/inducido químicamente , Cistitis Intersticial/genética , Cistitis Intersticial/metabolismo , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Interleucina-6/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Peroxidasa/metabolismo , Receptor Muscarínico M2/genética , Receptor Muscarínico M2/metabolismo , Receptor Muscarínico M3/genética , Receptor Muscarínico M3/metabolismo , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/genética , Factor de Necrosis Tumoral alfa/metabolismo , Vejiga Urinaria/metabolismo , Vejiga Urinaria/fisiopatología , Micción/efectos de los fármacos , Urodinámica/efectos de los fármacosRESUMEN
A significant number of experimental and clinical studies published in peer-reviewed journals have demonstrated promising pharmacological properties of capsaicin in relieving signs and symptoms of non-communicable diseases (chronic diseases). This chapter provides an overview made from basic and clinical research studies of the potential therapeutic effects of capsaicin, loaded in different application forms, such as solution and cream, on chronic diseases (e.g. arthritis, chronic pain, functional gastrointestinal disorders and cancer). In addition to the anti-inflammatory and analgesic properties of capsaicin largely recognized via, mainly, interaction with the TRPV1, the effects of capsaicin on different cell signalling pathways will be further discussed here. The analgesic, anti-inflammatory or apoptotic effects of capsaicin show promising results in arthritis, neuropathic pain, gastrointestinal disorders or cancer, since evidence demonstrates that the oral or local application of capsaicin reduce inflammation and pain in rheumatoid arthritis, promotes gastric protection against ulcer and induces apoptosis of the tumour cells. Sadly, these results have been paralleled by conflicting studies, which indicate that high concentrations of capsaicin are likely to evoke deleterious effects, thus suggesting that capsaicin activates different pathways at different concentrations in both human and rodent tissues. Thus, to establish effective capsaicin doses for chronic conditions, which can be benefited from capsaicin therapeutic effects, is a real challenge that must be pursued.
Asunto(s)
Analgésicos/uso terapéutico , Antiinflamatorios/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Capsaicina/uso terapéutico , Enfermedad Crónica/tratamiento farmacológico , Descubrimiento de Drogas/métodos , Analgésicos/efectos adversos , Analgésicos/química , Animales , Antiinflamatorios/efectos adversos , Antiinflamatorios/química , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/química , Capsaicina/efectos adversos , Capsaicina/química , Relación Dosis-Respuesta a Droga , Humanos , Fitoterapia , Plantas Medicinales , Transducción de Señal/efectos de los fármacosRESUMEN
Hydrogen sulfide exerts a number of cytoprotective and anti-inflammatory effects in many organ systems. In an effort to exploit these potent and beneficial effects, a number of hydrogen sulfide-releasing derivatives of existing drugs have been developed and extensively tested in pre-clinical models. In particular, efforts have been made by several groups to develop hydrogen sulfide-releasing derivatives of a number of nonsteroidal anti-inflammatory drugs. The main goal of this approach is to reduce the gastrointestinal ulceration and bleeding caused by this class of drugs, particularly when used chronically such as in the treatment of arthritis. However, these drugs may also have utility for prevention of various types of cancer. This paper provides an overview of some of the mechanisms underlying the anti-inflammatory and cytoprotective actions of hydrogen sulfide. It also gives some examples of hydrogen sulfide-releasing anti-inflammatory drugs, and their actions in terms of reducing inflammation and attenuating the development of cancer in experimental models.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Antineoplásicos/farmacología , Sulfuro de Hidrógeno/química , Sulfuro de Hidrógeno/farmacología , Sustancias Protectoras/farmacología , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacocinética , Antineoplásicos/química , Antineoplásicos/farmacocinética , Descubrimiento de Drogas , Humanos , Sulfuro de Hidrógeno/farmacocinética , Sustancias Protectoras/química , Sustancias Protectoras/farmacocinéticaRESUMEN
OBJECTIVE: intra-articular co-injection of kaolin with carrageenan (CGN) in rodents is widely used as an experimental model of arthritis. However, the ability of kaolin to cause arthritis and related immune responses when administered alone is unclear. We evaluated the contribution of prostanoids and sensory C-fibres (and their neuropeptide substance P) to kaolin-induced inflammation in the rat knee. METHODS: Wistar rats, 8-10 weeks old, received an intra-articular injection of kaolin (1-10 µg/joint) or saline into the knee joint. Knee inflammation, proinflammatory cytokines, pain behaviour and secondary tactile allodynia were assessed over 5 h, when synovial leukocyte counts, histopathological changes and proinflammatory cytokine levels were evaluated. RESULTS: The intra-articular injection of kaolin caused a dose- and time-dependent knee swelling and impairment of motion that were associated with secondary tactile allodynia, elevated concentrations of IL-1ß, IL-6 and TNFα, leukocyte infiltration, and histopathological changes in the ipsilateral hindpaw. The neurokinin-1 (NK1) receptor antagonist SR140333 or neonatal treatment with capsaicin markedly reduced the inflammatory parameters, cytokines and allodynia but failed to significantly inhibit the impaired motion. The cyclo-oxygenase inhibitor indomethacin partially inhibited knee oedema and allodynia but did not affect the leukocyte influx, myeloperoxidase activity or impaired motion in the kaolin-injected rat. CONCLUSIONS: We show the first evidence that intra-articular injection of kaolin without CGN produced severe acute monoarthritis. This was highly dependent on substance P (released from C-fibres) and NK1 receptor activation, which stimulated local production of proinflammatory cytokines. This model may be of critical importance for mechanistic studies and screening new anti-inflammatory/analgesic drugs.
Asunto(s)
Antidiarreicos/toxicidad , Artritis/inducido químicamente , Caolín/toxicidad , Receptores de Neuroquinina-1/metabolismo , Animales , Animales Recién Nacidos , Artritis/complicaciones , Artritis/tratamiento farmacológico , Capsaicina/toxicidad , Citocinas/metabolismo , Modelos Animales de Enfermedad , Edema/etiología , Inhibidores Enzimáticos/uso terapéutico , Hiperalgesia/etiología , Indometacina/uso terapéutico , Articulación de la Rodilla/patología , Masculino , Dimensión del Dolor , Peroxidasa/metabolismo , Piperidinas/uso terapéutico , Quinuclidinas/uso terapéutico , Ratas , Ratas Wistar , Líquido Sinovial/metabolismoRESUMEN
Thousands of people suffer from severe malaria every year. The innate immune response plays a determinant role in host's defence to malaria. Transient receptor potential vanilloid 1 (TRPV1) modulates macrophage-mediated responses in sepsis, but its role in other pathogenic diseases has never been addressed. We investigated the effects of capsazepine, a TRPV1 antagonist, in malaria. C57BL/6 mice received 10(5) red blood cells infected with Plasmodium berghei ANKA intraperitoneally. Noninfected mice were used as controls. Capsazepine or vehicle was given intraperitoneally for 6 days. Mice were culled on day 7 after infection and blood and spleen cell phenotype and activation were evaluated. Capsazepine decreased circulating but not spleen F4/80(+)Ly6G(+) cell numbers as well as activation of both F4/80(+)and F4/80(+)Ly6G(+) cells in infected animals. In addition, capsazepine increased circulating but not spleen GR1(+) and natural killer (NK) population, without interfering with natural killer T (NKT) cell numbers and blood NK and NKT activation. However, capsazepine diminished CD69 expression in spleen NKT but not NK cells. Infection increased lipid peroxidation and the release of TNFα and IFNγ, although capsazepine-treated group exhibited lower levels of lipid peroxidation and TNFα. Capsazepine treatment did not affect parasitaemia. Overall, TRPV1 antagonism modulates the innate immune response to malaria.
Asunto(s)
Capsaicina/análogos & derivados , Plasmodium berghei/patogenicidad , Canales Catiónicos TRPV/antagonistas & inhibidores , Animales , Capsaicina/uso terapéutico , Citometría de Flujo , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Interleucina-4/metabolismo , Interleucina-6/metabolismo , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Plasmodium berghei/inmunologíaRESUMEN
Aedes aegypti (Ae. aegypti) saliva induces a variety of anti-inflammatory and immunomodulatory activities. Interestingly, although it is known that mosquito bites cause allergic reactions in sensitised hosts, the primary exposure of humans to Ae. aegypti does not evoke significant itching. Whether active components in the saliva of Ae. aegypti can counteract the normal itch reaction to injury produced by a histaminergic or non-histaminergic pathway in vertebrate hosts is unknown. This study investigated the effects of Ae. aegypti mosquito salivary gland extract (SGE) on sensitive reactions such as itching and associated skin inflammation. Acute pruritus and plasma extravasation were induced in mice by the intradermal injection of either compound 48/80 (C48/80), the Mas-related G protein-coupled receptor (Mrgpr) agonist chloroquine (CQ), or the transient receptor potential ankyrin 1 (TRPA1) agonist allyl isothiocyanate (AITC). The i.d. co-injection of Ae. aegypti SGE inhibited itching, plasma extravasation, and neutrophil influx evoked by C48/80, but it did not significantly affect mast cell degranulation in situ or in vitro. Additionally, SGE partially reduced CQ- and AITC-induced pruritus in vivo, suggesting that SGE affects pruriceptive nerve firing independently of the histaminergic pathway. Activation of TRPA1 significantly increased intracellular Ca2+ in TRPA-1-transfected HEK293t lineage, which was attenuated by SGE addition. We showed for the first time that Ae. aegypti SGE exerts anti-pruriceptive effects, which are partially regulated by the histamine-independent itch TRPA1 pathway. Thus, SGE may possess bioactive molecules with therapeutic potential for treating nonhistaminergic itch.
RESUMEN
The combustion of fossil fuels contributes to air pollution (AP), which was linked to about 8.79 million global deaths in 2018, mainly due to respiratory and cardiovascular-related effects. Among these, particulate air pollution (PM2.5) stands out as a major risk factor for heart health, especially during vulnerable phases. Our prior study showed that premature exposure to 1,2-naphthoquinone (1,2-NQ), a chemical found in diesel exhaust particles (DEP), exacerbated asthma in adulthood. Moreover, increased concentration of 1,2-NQ contributed to airway inflammation triggered by PM2.5, employing neurogenic pathways related to the up-regulation of transient receptor potential vanilloid 1 (TRPV1). However, the potential impact of early-life exposure to 1,2-naphthoquinone (1,2-NQ) on atrial fibrillation (AF) has not yet been investigated. This study aims to investigate how inhaling 1,2-NQ in early life affects the autonomic adrenergic system and the role played by TRPV1 in these heart disturbances. C57Bl/6 neonate male mice were exposed to 1,2-NQ (100 nM) or its vehicle at 6, 8, and 10 days of life. Early exposure to 1,2-NQ impairs adrenergic responses in the right atria without markedly affecting cholinergic responses. ECG analysis revealed altered rhythmicity in young mice, suggesting increased sympathetic nervous system activity. Furthermore, 1,2-NQ affected ß1-adrenergic receptor agonist-mediated positive chronotropism, which was prevented by metoprolol, a ß1 receptor blocker. Capsazepine, a TRPV1 blocker but not a TRPC5 blocker, reversed 1,2-NQ-induced cardiac changes. In conclusion, neonate mice exposure to AP 1,2-NQ results in an elevated risk of developing cardiac adrenergic dysfunction, potentially leading to atrial arrhythmia at a young age.
Asunto(s)
Contaminantes Atmosféricos , Naftoquinonas , Masculino , Animales , Ratones , Contaminantes Atmosféricos/toxicidad , Adrenérgicos , Células Receptoras Sensoriales , Atrios Cardíacos , PolvoRESUMEN
Mitochondria-targeted hydrogen sulfide (H2S) donor compounds, such as compound AP39, supply H2S into the mitochondrial environment and have shown several beneficial in vitro and in vivo effects in cardiovascular conditions such as diabetes and hypertension. However, the study of their direct vascular effects has not been addressed to date. Thus, the objective of the present study was to analyze the effects and describe the mechanisms of action of AP39 on the in vitro vascular reactivity of mouse mesenteric artery. Protein and gene expressions of the H2S-producing enzymes (CBS, CSE, and 3MPST) were respectively analyzed by Western blot and qualitative RT-PCR, as well the in vitro production of H2S by mesenteric artery homogenates. Gene expression of CSE and 3MPST in the vessels has been evidenced by RT-PCR experiments, whereas the protein expression of all the three enzymes was demonstrated by Western blotting experiments. Nonselective inhibition of H2S-producing enzymes by AOAA abolished H2S production, whereas it was partially inhibited by PAG (a CSE selective inhibitor). Vasorelaxation promoted by AP39 and its H2S-releasing moiety (ADT-OH) were significantly reduced after endothelium removal, specifically dependent on NO-cGMP signaling and SKCa channel opening. Endogenous H2S seems to participate in the mechanism of action of AP39, and glibenclamide-induced KATP blockade did not affect the vasorelaxant response. Considering the results of the present study and the previously demonstrated antioxidant and bioenergetic effects of AP39, we conclude that mitochondria-targeted H2S donors may offer a new promising perspective in cardiovascular disease therapeutics.
Asunto(s)
Arterias Mesentéricas , Vasodilatadores , Animales , Ratones , Mitocondrias/metabolismo , Tionas , Vasodilatadores/farmacologíaRESUMEN
Orofacial pain is one of the commonest and most complex complaints in dentistry, greatly impairing life quality. Preclinical studies using monoterpenes have shown pharmacological potential to treat painful conditions, but the reports of the effects of myrtenol on orofacial pain and inflammation are scarce. The aim of this study was to evaluate the effect of myrtenol in experimental models of orofacial pain and inflammation. Orofacial nociceptive behavior and the immunoreactivity of the phosphorylated p38 (P-p38)-MAPK in trigeminal ganglia (TG) and spinal trigeminal subnucleus caudalis (STSC) were determined after the injection of formalin in the upper lip of male Swiss mice pretreated with myrtenol (12.5 and 25 mg/kg, i.p.) or vehicle. Orofacial inflammation was induced by the injection of carrageenan (CGN) in the masseter muscle of mice pretreated with myrtenol (25 and 50 mg/kg, i.p.) or its vehicle (0.02% Tween 80 in saline). Myeloperoxidase (MPO) activity and histopathological changes in the masseter muscle and interleukin (IL)-1ß levels in the TG and STSC were measured. The increase in face-rubbing behavior time induced by formalin and P-p38-MAPK immunostaining in trigeminal ganglia were significantly reduced by myrtenol treatment (12.5 and 25 mg/kg). Likewise, increased MPO activity and inflammatory histological scores in masseter muscle, as well as augmented levels of IL-1ß in the TG AND STSC, observed after CGN injection, were significantly decreased by myrtenol (25 and 50 mg/kg). Myrtenol has potential to treat orofacial inflammation and pain, which is partially related to IL-1ß levels in the trigeminal pathway and p38-MAPK modulation in trigeminal ganglia.
RESUMEN
Lipopolysaccharide (LPS) is a component of gram-negative bacteria wall that elicits inflammatory response in the host through the toll-like receptor 4 (TLR4) activation. In the lower urinary tract (LUT), bacteria-derived LPS has been associated with lower urinary tract symptoms (LUTS); however, little is known about the effects of LPS in the urethral smooth muscle (USM). In the present study, we evaluated the functional and molecular effects of LPS in mouse USM in vitro, focusing on the LPS-induced TLR4-signaling pathway. Male C57BL6/JUnib and TLR4 knockout mice (TLR4 KO) were used. The USM contraction was performed in the presence of LPS (62.5-500 µg/mL), indomethacin (10 µM), L-NAME (100 µM), and TAK 242 (1 µM). The RT-PCR assay for the IL-1ß, NF-kB, and COX-2 genes was also evaluated in the presence of LPS (125 µg/mL) and caspase 1 inhibitor (20 µM). Our results showed that LPS reduces mouse USM contraction elicited by phenylephrine and vasopressin. This LPS-induced urethral inhibitory effect was not reversed by the TLR4 inhibition or its absence in the TLR4 KO mice. Conversely, indomethacin (but not L-NAME) reversed the LPS-induced USM hypocontractility. Molecular protocols indicated upregulation of IL-1ß, NF-kß, and COX-2 mRNA upon LPS incubation, which were blunted by caspase 1 inhibition. Our data showed that LPS reduced mouse USM contraction independently of TLR4 activation, involving caspase 1 and IL1ß, NF-kB, and COX-2 gene overexpression. Therefore, this alternative pathway might be a valuable target to reduce the LPS-induced urethral dysfunction under infection and inflammatory conditions.
Asunto(s)
Lipopolisacáridos , FN-kappa B , Animales , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Lipopolisacáridos/toxicidad , Masculino , Ratones , Músculo Liso/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Transducción de SeñalRESUMEN
Inflammatory arthritis, such as rheumatoid arthritis (RA), stands out as one of the main sources of pain and impairment to the quality of life. The use of hemopressin (PVNFKFLSH; Hp), an inverse agonist of type 1 cannabinoid receptor, has proven to be effective in producing analgesia in pain models, but its effect on neuro-inflammatory aspects of RA is limited. In this study, antigen-induced arthritis (AIA) was evoked by the intraarticular (i.art.) injection of methylated bovine serum albumin (mBSA) in male Sprague Dawley rats. Phosphate buffered saline (PBS)-injected ipsilateral knee joints or AIA contralateral were used as control. Nociceptive and inflammatory parameters such as knee joint oedema and leukocyte influx and histopathological changes were carried out in addition to the local measurement of interleukins (IL) IL-6, IL-1ß, tumor necrosis factor-α and the immunoreactivity of the neuropeptides substance P (SP) and calcitonin gene related peptide (CGRP) in the spinal cord (lumbar L3-5 segments) of AIA rats. For 4 days, AIA rats were treated daily with a single administration of saline, Hp injected (10 or 20 µg/day, i.art.), Hp given orally (20 µg/Kg, p.o.) or indomethacin (Indo; 5 mg/Kg, i.p.). In comparison to the PBS control group, the induction of AIA produced a significant and progressive mono-arthritis condition. The degree of AIA severity progressively compromised the normal walking pattern and impaired mobility over the next four days in relation to PBS-injected rats or contralateral knee joints. In AIA rats, the reduction of the distance between footprints and disturbances of gait evidenced signs of nociception. This response worsened at day 4, and a loss of footprint from the ipsilateral hind paw was evident. Daily treatment of the animals with Hp either i.art. (10 and 20 µg/knee) or p.o. (20 µg/Kg) as well as Indo (5 mg/Kg, i.p.) ameliorated the impaired mobility in a time-dependent manner (P < 0.05). In parallel, the AIA-injected ipsilateral knee joints reach a peak of swelling 24 h after AIA induction, which persisted over the next four days in relation to PBS-injected rats or contralateral knee joints. There was a significant but not dose-dependent inhibitory effect produced by all dosages and routes of Hp treatments on AIA-induced knee joint swelling (P < 0.05). In addition, the increased synovial levels of MPO activity, total leukocytes number and IL-6, but not IL-1ß, were significantly reduced by the lower i.art. dose of Hp. In conclusion, these results successfully demonstrate that Hp may represent a novel therapeutic strategy to treat RA, an effect which is unrelated to the proinflammatory actions of the neuropeptides CGRP and SP.
Asunto(s)
Antiinflamatorios/farmacología , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Hemoglobinas/farmacología , Dolor Nociceptivo/prevención & control , Fragmentos de Péptidos/farmacología , Administración Oral , Animales , Antiinflamatorios/administración & dosificación , Conducta Animal/efectos de los fármacos , Citocinas/metabolismo , Edema/tratamiento farmacológico , Marcha/efectos de los fármacos , Hemoglobinas/administración & dosificación , Inflamación/tratamiento farmacológico , Inyecciones Intraarticulares , Articulación de la Rodilla/efectos de los fármacos , Articulación de la Rodilla/metabolismo , Articulación de la Rodilla/patología , Leucocitos/efectos de los fármacos , Masculino , Fragmentos de Péptidos/administración & dosificación , Ratas Sprague-Dawley , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Sustancia P/metabolismoRESUMEN
The environmental chemical 1,2-naphthoquinone (1,2-NQ) is implicated in the exacerbation of airways diseases induced by exposure to diesel exhaust particles (DEP), which involves a neurogenic-mediated mechanism. Plasma extravasation in trachea, main bronchus and lung was measured as the local (125)I-bovine albumin accumulation. RT-PCR quantification of TRPV1 and tachykinin (NK(1) and NK(2)) receptor gene expression were investigated in main bronchus. Intratracheal injection of DEP (1 and 5 mg/kg) or 1,2-NQ (35 and 100 nmol/kg) caused oedema in trachea and bronchus. 1,2-NQ markedly increased the DEP-induced responses in the rat airways in an additive rather than synergistic manner. This effect that was significantly reduced by L-732,138, an NK(1) receptor antagonist, and in a lesser extent by SR48968, an NK(2) antagonist. Neonatal capsaicin treatment also markedly reduced DEP and 1,2-NQ-induced oedema. Exposure to pollutants increased the TRPV1, NK(1) and NK(2) receptors gene expression in bronchus, an effect was partially suppressed by capsaicin treatment. In conclusion, our results are consistent with the hypothesis that DEP-induced airways oedema is highly influenced by increased ambient levels of 1,2-NQ and takes place by neurogenic mechanisms involving up-regulation of TRPV1 and tachykinin receptors.
Asunto(s)
Naftoquinonas/toxicidad , Neuronas Aferentes/efectos de los fármacos , Sistema Respiratorio/efectos de los fármacos , Canales Catiónicos TRPV/metabolismo , Emisiones de Vehículos/toxicidad , Contaminantes Atmosféricos/toxicidad , Animales , Femenino , Inflamación/metabolismo , Masculino , Neuronas Aferentes/metabolismo , Ratas , Ratas Wistar , Sistema Respiratorio/inervación , Sistema Respiratorio/metabolismoRESUMEN
Extensive literature regarding the health side effects of ambient pollutants (AP) are available, such as diesel exhaust particles (DEPs), but limited studies are available on their electrophilic contaminant 1,2-Naphthoquinone (1,2-NQ), enzymatically derived from naphthalene. This review summarizes relevant toxicologic and biological properties of 1,2-NQ as an environmental pollutant or to a lesser degree as a backbone in drug development to treat infectious diseases. It presents evidence of 1,2-NQ-mediated genotoxicity, neurogenic inflammation, and cytotoxicity due to several mechanistic properties, including the production of reactive oxygen species (ROS), that promote cell damage, carcinogenesis, and cell death. Many signal transduction pathways act as a vulnerable target for 1,2-NQ, including kappaB kinase b (IKKbeta) and protein tyrosine phosphatase 1B (PTP1B). Antioxidant molecules act in defense against ROS/RNS-mediated 1,2-NQ responses to injury. Nonetheless, its inhibitory effects at PTP1B, altering the insulin signaling pathway, represents a new therapeutic target to treat diabetes type 2. Questions exist whether exposure to 1,2-NQ may promote arylation of the Keap1 factor, a negative regulator of Nrf2, as well as acting on the sepiapterin reductase activity, an NADPH-dependent enzyme which catalyzes the formation of critical cofactors in aromatic amino acid metabolism and nitric oxide biosynthesis. Exposure to 1,2-NQ is linked to neurologic, behavioral, and developmental disturbances as well as increased susceptibility to asthma. Limited new knowledge exists on molecular modeling of quinones molecules as antitumoral and anti-microorganism agents. Altogether, these studies suggest that 1,2-NQ and its intermediate compounds can initiate a number of pathological pathways as AP in living organisms but it can be used to better understand molecular pathways.
RESUMEN
Skin diseases constitute a major health problem affecting a high proportion of the population every day and have different aetiologies that include inflammation, infections, and tumours. Hydrogen sulfide (H2 S) is a gaseous signalling molecule recognized as a gasotransmitter together with NO and carbon monoxide. Under physiological conditions, H2 S is produced in the skin by enzymic pathways and plays a physiological role in a variety of functions, such as vasodilatation, cell proliferation, apoptosis, and inflammation. Alterations of H2 S production are implicated in a variety of dermatological diseases, such as psoriasis, melanoma, and other dermatoses. On the other hand, H2 S-releasing-based therapies based on H2 S donor compounds are being developed to treat some of these situations. In this review, we provide an up-to-date overview of the role of H2 S in the normal skin and its clinical and pathological significance, as well as the therapeutic potential of different H2 S donors for treatment of skin diseases. LINKED ARTICLES: This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc.
Asunto(s)
Gasotransmisores , Sulfuro de Hidrógeno , Transducción de SeñalRESUMEN
Aims: The covalent linking of nonsteroidal anti-inflammatory drugs to a hydrogen sulfide (H2S)-releasing moiety has been shown to dramatically reduce gastrointestinal (GI) damage and bleeding, as well as increase anti-inflammatory and analgesic potency. We have tested the hypothesis that an H2S-releasing derivative of ketoprofen (ATB-352) would exhibit enhanced efficacy without significant GI damage in a mouse model of allodynia/hyperalgesia. Results: ATB-352 was significantly more potent and effective as an analgesic than ketoprofen and did not elicit GI damage. Pretreatment with an antagonist of the CB1 cannabinoid receptor (AM251) significantly reduced the analgesic effects of ATB-352. The CB1 antagonist exacerbated GI damage when coadministered with ketoprofen, but GI damage was not induced by the combination of ATB-352 and the CB1 antagonist. In vitro, ATB-352 was substantially more potent than ketoprofen as an inhibitor of fatty acid amide hydrolase, consistent with a contribution of endogenous cannabinoids to the analgesic effects of this drug. Blood anandamide levels were significantly depressed by ketoprofen, but remained unchanged after treatment with ATB-352. Innovation: Ketoprofen is a potent analgesic, but its clinical use, even in the short term, is significantly limited by its propensity to cause significant ulceration and bleeding in the GI tract. Covalently linking an H2S-releasing moiety to ketoprofen profoundly reduces the GI toxicity of the drug, while boosting analgesic effectiveness. Conclusion: This study demonstrates a marked enhancement of the potency and effectiveness of ATB-352, an H2S-releasing derivative of ketoprofen, in part, through the involvement of the endogenous cannabinoid system. This may have significant advantages for the control and management of pain, such as in a postoperative setting.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Tracto Gastrointestinal/efectos de los fármacos , Sulfuro de Hidrógeno/farmacología , Analgésicos/farmacología , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/química , Cannabinoides/metabolismo , Cannabinoides/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta en la Radiación , Sinergismo Farmacológico , Ácidos Grasos/metabolismo , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Sulfuro de Hidrógeno/efectos adversos , Sulfuro de Hidrógeno/química , Cetoprofeno/farmacología , Ratones , Dolor/tratamiento farmacológico , Dolor/etiologíaRESUMEN
Stings by Polistes wasps can cause life-threatening allergic reactions, pain and inflammation. We examined the changes in microvascular permeability and neutrophil influx caused by the venom of Polistes lanio a paper wasp found in southeastern Brazil. The intradermal injection of wasp venom caused long-lasting paw oedema and dose-dependently increased microvascular permeability in mouse dorsal skin. SR140333, an NK(1) receptor antagonist, markedly inhibited the response, but the NK(2) receptor antagonist SR48968 was ineffective. The oedema was reduced in capsaicin-treated rats, indicating a direct activation of sensory fibres. Dialysis of the venom partially reduced the oedema and the remaining response was further inhibited by SR140333. Mass spectrometric analysis of the venom revealed two peptides (QPPTPPEHRFPGLM and ASEPTALGLPRIFPGLM) with sequence similarities to the C-terminal region of tachykinin-like peptides found in Phoneutria nigriventer spider venom and vertebrates. Wasp venom failed to release histamine from mast cells in vitro and spectrofluorometric assay of the venom revealed a negligible content of histamine in the usual dose of P. l. lanio venom (1nmol of histamine/7mug of venom) that was removed by dialysis. The histamine H(1) receptor antagonist pyrilamine, but not bradykinin B(1) or B(2) receptor antagonists, inhibited venom-induced oedema. In conclusion, P. l. lanio venom induces potent oedema and increases vascular permeability in mice, primarily through activation of tachykinin NK(1) receptors by substance P released from sensory C fibres, which in turn releases histamine from dermal mast cells. This is the first description of a neurovascular mechanism for P. l. lanio venom-mediated inflammation. The extent to which the two tachykinin-like peptides identified here contribute to this neurogenic inflammatory response remains to be elucidated.
Asunto(s)
Inflamación/inducido químicamente , Piel/efectos de los fármacos , Venenos de Avispas/toxicidad , Avispas/fisiología , Secuencia de Aminoácidos , Animales , Permeabilidad Capilar/efectos de los fármacos , Edema/inducido químicamente , Histamina/metabolismo , Metaloproteasas/metabolismo , Ratones , Ratas , Receptores de Taquicininas/metabolismo , Taquicininas/química , Taquicininas/metabolismo , Taquicininas/farmacologíaRESUMEN
Studies suggest that hydrogen sulfide (H2S) plays a relevant and beneficial role in the pathophysiology of pulmonary allergic diseases, such as asthma. These diseases may be triggered by changes in airway epithelium caused by repeated exposure to environmental allergens. This study aimed to investigate whether H2S protects against bronchial epithelium apoptosis in allergic inflammation in mice. The effects of H2S on the production of Th2 cytokines and on the infiltration of pulmonary inflammatory cells were also studied. Female BALB/c mice previously sensitized with ovalbumin (OVA) were treated with H2S donor (sodium hydrosulfide [NaHS]) 30â¯min prior to OVA challenge. After euthanasia (48â¯h post challenge), the right lung was homogenized to study apoptosis protein expression and to analyze cytokine levels in lung tissue. The left lobe was fixed in formalin for morphological analysis of lung tissue and verification of apoptosis in situ by the TUNEL assay. Histological results showed that NaHS reduced the airway inflammatory infiltrate and prevented an increase in the IL-4, IL-5 and IL-25 levels caused by OVA challenge. Activation of caspase 3 and FasL in response to the allergen was also fully prevented by NaHS treatment. TUNEL staining showed that the challenge from OVA significantly increased the rate of apoptosis in the bronchiolar epithelium, and that this incremental apoptosis was abolished by NaHS treatment. In conclusion, our results showed that H2S donor has a protective effect against airway epithelium damage caused by an allergic reaction, and represents a potential agent in treating allergic lung disorders, such as asthma.
Asunto(s)
Citocinas/inmunología , Epitelio/efectos de los fármacos , Pulmón/efectos de los fármacos , Hipersensibilidad Respiratoria/inmunología , Animales , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Epitelio/inmunología , Epitelio/patología , Femenino , Sulfuro de Hidrógeno , Pulmón/inmunología , Pulmón/patología , Ratones Endogámicos BALB C , Ovalbúmina , Hipersensibilidad Respiratoria/patología , Sulfuros/farmacologíaRESUMEN
Because P-glycoprotein (P-gp) plays an absorptive role in the skin, its pharmacological inhibition represents a strategy to promote cutaneous localization of anticancer agents that serve as its substrates, improving local efficacy while reducing systemic exposure. Here, we evaluated the ability of a nanoemulsion (NE) coencapsulating a P-gp inhibitor (elacridar) with the antitumor drug paclitaxel to promote epidermal targeting. Loaded NE displayed a nanometric size (45.2 ± 4.0 nm) and negative zeta potential (-4.2 ± 0.8 mV). Elacridar improved NE ability to inhibit verapamil-induced ATPase activity of P-gp; unloaded NE-inhibited P-gp when used at a concentration of 1500 µM, while elacridar encapsulation decreased this concentration by 3-fold (p <0.05). Elacridar-loaded NE reduced paclitaxel penetration into the dermis of freshly excised mice skin and its percutaneous permeation by 1.5- and 1.7-fold (p <0.05), respectively at 6 h, whereas larger drug amounts (1.4-fold, p <0.05) were obtained in viable epidermis. Assessment of cutaneous distribution of a fluorescent paclitaxel derivative confirmed the smaller delivery into the dermis at elacridar presence. In conclusion, we have provided novel evidence that NE containing elacridar exhibited a clear potential for P-gp inhibition and enabled epidermal targeting of paclitaxel, which in turn, can potentially reduce adverse effects associated with systemic exposure to anticancer therapy.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Acridinas/farmacología , Antineoplásicos/farmacología , Portadores de Fármacos/química , Proteínas de Transporte de Membrana/metabolismo , Nanopartículas/química , Piel/efectos de los fármacos , Tetrahidroisoquinolinas/farmacología , Acridinas/química , Administración Cutánea , Animales , Antineoplásicos/química , Transporte Biológico/efectos de los fármacos , Emulsiones/química , Emulsiones/farmacología , Ratones , Ratones Endogámicos BALB C , Paclitaxel/química , Paclitaxel/farmacología , Tamaño de la Partícula , Tetrahidroisoquinolinas/química , Verapamilo/química , Verapamilo/farmacologíaRESUMEN
We investigated the effect of the crude herbal extract from Uncaria tomentosa (UT) on non-alcoholic fatty liver disease (NAFLD) in two models of obesity: high fat diet (HFD) and genetically obese (ob/ob) mice. Both obese mouse models were insulin resistant and exhibited an abundance of lipid droplets in the hepatocytes and inflammatory cell infiltration in the liver, while only the HFD group had collagen deposition in the perivascular space of the liver. UT treatment significantly reduced liver steatosis and inflammation in both obese mouse models. Furthermore, serine phosphorylation of IRS-1 was reduced by 25% in the HFD mice treated with UT. Overall, UT treated animals exhibited higher insulin sensitivity as compared to vehicle administration. In conclusion, Uncaria tomentosa extract improved glucose homeostasis and reverted NAFLD to a benign hepatic steatosis condition and these effects were associated with the attenuation of liver inflammation in obese mice.