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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.
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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.
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Contaminantes Atmosféricos , Naftoquinonas , Masculino , Animales , Ratones , Contaminantes Atmosféricos/toxicidad , Adrenérgicos , Células Receptoras Sensoriales , Atrios Cardíacos , PolvoRESUMEN
Metabolic syndrome (MS) is a complex pathology characterized by visceral adiposity, insulin resistance, arterial hypertension, and dyslipidaemia. It has become a global epidemic associated with increased consumption of high-calorie, low-fibre food and sedentary habits. Some of its underlying mechanisms have been identified, with hypoadiponectinemia, inflammation and oxidative stress as important factors for MS establishment and progression. Alterations in adipokine levels may favour glucotoxicity and lipotoxicity which, in turn, contribute to inflammation and cellular stress responses within the adipose, pancreatic and liver tissues, in addition to hepatic steatosis. The multiple mechanisms of MS make its clinical management difficult, involving both non-pharmacological and pharmacological interventions. Transient receptor potential (TRP) channels are non-selective calcium channels involved in a plethora of physiological events, including energy balance, inflammation and oxidative stress. Evidence from animal models of disease has contributed to identify their specific contributions to MS and may help to tailor clinical trials for the disease. In this context, the oxidative stress sensors TRPV1, TRPA1 and TRPC5, play major roles in regulating inflammatory responses, thermogenesis and energy expenditure. Here, the interplay between these TRP channels and oxidative stress in MS is discussed in the light of novel therapies to treat this syndrome.
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Síndrome Metabólico , Canales de Potencial de Receptor Transitorio , Animales , Inflamación , Síndrome Metabólico/terapia , Estrés Oxidativo , Termogénesis , Canales de Potencial de Receptor Transitorio/metabolismoRESUMEN
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.
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Arterias Mesentéricas , Vasodilatadores , Animales , Ratones , Mitocondrias/metabolismo , Tionas , Vasodilatadores/farmacologíaRESUMEN
Metformin is the first-line drug to treat type 2 diabetes mellitus. Its mechanism of action is still debatable, and recent studies report that metformin attenuates oxidative stress. This study evaluated the in vitro antioxidant effects of a broad range of metformin concentrations on insulin-producing cells. The cell cycle, metabolism, glucose-stimulated insulin secretion, and cell death were evaluated to determine the biguanide effects on beta-cell function and survival. Antioxidant potential was based on reactive oxygen species (ROS), reduced glutathione (GSH), oxidative stress biomarker levels, and antioxidant enzyme and transcriptional factor Nrf2 activities. The results demonstrate that metformin disrupted GSIS in a concentration-dependent manner, lowered insulin content, and attenuated beta-cell metabolism. At high concentrations, metformin induced cell death and cell cycle arrest as well as increased ROS generation, consequently reducing GSH content. Although carbonylated protein content was elevated, indicating oxidative stress, the antioxidant enzyme and Nrf2 activities were not altered. In conclusion, our results show that metformin disrupts pancreatic beta-cell functionality but does not exert a putative antioxidant effect. It is important to note that the drug could potentially affect beta-cells, especially at high circulating levels.
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Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Metformina , Animales , Antioxidantes/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Metformina/farmacología , Metformina/uso terapéutico , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Ratas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Leukotrienes (LTs) participate in the process of tissue damage in periodontal disease by leukocyte chemotaxis and osteoclastic activation. The activation of Cysteinyl-LT receptor is associated with increased expression of proinflammatory molecules and osteoclastogenesis. However, its implications on periodontal disease progression have not been studied. The present study evaluated the effect of the cysteinyl-LT receptor antagonist (montelukast [MT]) on ligature-induced experimental periodontitis (EP) in rats. METHODS: Adult male Wistar rats were subjected to bilateral ligature-induced periodontitis and orally treated with MT (at doses of 10 or 30 mg/kg/d, MT10, and MT30, respectively). Sham animals had the ligatures immediately removed and received placebo treatment. Sets of animals were euthanized 7, 14, or 21 days after ligature placement and the mandibles were removed for macroscopic evaluation of alveolar bone loss (ABL). In addition, histological analysis of periodontal tissues, myeloperoxidase (MPO) activity of gingival tissues, and periodontal tissue expression of collagen type I, RUNX2, RANK, RANKL, OPG, BLT1, Cys-LTR1, LTA4H, and LTC4S were also analyzed. RESULTS: MT significantly reduced ABL at 14 (MT10 and MT30) and 21 days (MT10) (P < 0.05), gingival MPO at 7 (MT10) and 14 days (MT30) (P < 0.05), LTA4H, BLT1 and LTC4S gene expression on day 14 day (MT30, P < 0.05) and increased RUNX2 expression on day 14 (MT30, P < 0.05). CONCLUSION: Systemic therapy with MT decreases periodontal inflammation and ABL in ligature-induced periodontitis in rats.
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Pérdida de Hueso Alveolar , Periodontitis , Pérdida de Hueso Alveolar/tratamiento farmacológico , Pérdida de Hueso Alveolar/prevención & control , Animales , Inflamación , Antagonistas de Leucotrieno , Masculino , Periodontitis/tratamiento farmacológico , Ratas , Ratas WistarRESUMEN
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.
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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
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.
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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.
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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
BACKGROUND AND PURPOSE: ATB-346 is a hydrogen sulfide (H2 S)-releasing anti-inflammatory and analgesic drug. Animal studies demonstrated negligible gastrointestinal (GI) damage despite marked inhibition of COX activity and significant analgesic and anti-inflammatory effects. In humans, ATB-346 (250 mg once daily) was found to inhibit COX to the same extent as naproxen (550 mg twice daily). EXPERIMENTAL APPROACH: Two hundred forty-four healthy volunteers completed a 2-week, double-blind study, taking either ATB-346 (250 mg once daily) or naproxen (550 mg twice daily), with upper GI ulceration being examined endoscopically. KEY RESULTS: Forty-two per cent of the subjects taking naproxen developed at least one ulcer (≥3-mm diameter), while only 3% of the subjects taking ATB-346 developed at least one ulcer. The two drugs produced comparable and substantial (>94%) suppression of COX activity. Subjects in the naproxen group developed more ulcers per subject than ATB-346-treated subjects and a greater incidence of larger ulcers (≥5-mm diameter). The incidence of dyspepsia, abdominal pain, gastro-oesophageal reflux, and nausea was lower with ATB-346 than with naproxen. Subjects treated with ATB-346 had significantly higher plasma levels of H2 S than those treated with naproxen. CONCLUSIONS AND IMPLICATIONS: This Phase 2B study provides unequivocal evidence for a marked reduction of GI toxicity of the H2 S-releasing analgesic/anti-inflammatory drug, ATB-346, as compared to the conventional dose of naproxen that produced equivalent suppression of COX. 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.
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Sulfuro de Hidrógeno , Preparaciones Farmacéuticas , Animales , Antiinflamatorios , Antiinflamatorios no Esteroideos/efectos adversos , Inhibidores de la Ciclooxigenasa , Método Doble Ciego , Humanos , Naproxeno/efectos adversosRESUMEN
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.
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Gasotransmisores , Sulfuro de Hidrógeno , Transducción de SeñalRESUMEN
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.
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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
Hydrogen peroxide (H2O2)-based products are effective in tooth whitening; however, their safety is controversial as they may harm patient tissues/cells. These effects are suggested to be concentration-dependent; nonetheless, to date, there are no reports on H2O2-mediated oxidative damage in the gingival tissue, and neither whether this can be detected in gingival crevicular fluid (GCF) samples. We hypothesize that H2O2 whitening products may cause collateral oxidative tissue damage following in office application. Therefore, H2O2 and nitric oxide (NO) levels were investigated in GCF samples obtained from patients undergoing dental bleaching with H2O2 at different concentrations, in a randomized, double-blind, split-mouth clinical trial. A proteomic analysis of these samples was also performed. H2O2-based whitening products promoted inflammation which was detected in GCF samples and lasted for longer following 35% H2O2 bleaching. This included time-dependent changes in NO levels and in the abundance of proteins associated with NO synthesis, oxidative stress, neutrophil regulation, nucleic acid damage, cell survival and/or tissue regeneration. Overall, H2O2-based products used in office promote inflammation irrespective of their concentration. As the inflammation caused by 35% H2O2 is longer, patients may benefit better from using lower concentrations of this bleaching product, as they may result in less tissue damage.
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Líquido del Surco Gingival/metabolismo , Peróxido de Hidrógeno/metabolismo , Peróxido de Hidrógeno/farmacología , Blanqueadores Dentales/metabolismo , Blanqueadores Dentales/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Voluntarios Sanos , Humanos , Peróxido de Hidrógeno/administración & dosificación , Masculino , Neutrófilos/inmunología , Neutrófilos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Blanqueamiento de Dientes , Blanqueadores Dentales/administración & dosificaciónRESUMEN
BACKGROUND: Skeletal muscle inflammation is strongly associated with pain and may impair regeneration and functional recovery after injury. Since anti-inflammatory and antinociceptive effects have been described for the inclusion complex of carvacrol and ß-cyclodextrin (ßCD-carvacrol), this study investigated the effects of ßCD-carvacrol in a model of acute skeletal muscle inflammation. METHODS: Muscle injury was induced in male Wistar rats by injection of 3% carrageenan in the gastrocnemius muscle. Rats were orally pretreated with saline (vehicle) or ßCD-carvacrol (20, 40, 80 and 180 mg/kg) one hour before administration of carrageenan. RESULTS: The injection of carrageenan in the gastrocnemius muscle increased tissue myeloperoxidase (MPO) activity (p < 0.001), edema (p < 0.001) and the levels of tumoral necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, macrophage inflammatory protein (MIP-2), but not IL-10 levels. Also, it increased mechanical hyperalgesia and decreased the grip force of animals. Pretreatment with ßCD-carvacrol (80 or 160 mg/kg) significantly decreased muscle MPO activity and edema 24 h after injury in comparison to vehicle-pretreated group. Animals pretreated with ßCD-carvacrol (160 mg/kg) presented significantly lower levels of IL-1ß, IL-6 and MIP-2 and higher levels of IL-10 six hours after induction and lower levels of TNF-α and MIP-2 after 24 h when compared to the vehicle group. Pretreatment with ßCD-carvacrol also reduced mechanical hyperalgesia and limited the decrease of grip force (80 or 160 mg/kg; p < 0.001) 6 and 24 h after injury. CONCLUSION: These results show that ßCD-carvacrol reduces inflammation and nociception in a model of acute injury to skeletal muscles.
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Mediadores de Inflamación/metabolismo , Monoterpenos/administración & dosificación , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Nocicepción/efectos de los fármacos , beta-Ciclodextrinas/administración & dosificación , Animales , Carragenina/toxicidad , Cimenos , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Fuerza de la Mano/fisiología , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Mediadores de Inflamación/antagonistas & inhibidores , Masculino , Nocicepción/fisiología , Ratas , Ratas WistarRESUMEN
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.
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Uña de Gato/metabolismo , Resistencia a la Insulina/fisiología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Animales , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Inflamación/tratamiento farmacológico , Insulina/farmacología , Hígado/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Obesidad/fisiopatología , Extractos Vegetales/farmacologíaRESUMEN
Mesenchymal stromal cells (MSCs) are multipotent cells with abilities to exert immunosuppressive response promoting tissue repair. Studies have shown that MSCs can secrete extracellular vesicles (MVs-MSCs) with similar regulatory functions to the parental cells. Furthermore, strong evidence suggesting that MVs-MSCs can modulate several immune cells (i.e., Th1, Th17, and Foxp3+ T cells). However, their precise effect on macrophages (MÏs) remains unexplored. We investigated the immunoregulatory effect of MVs-MSCs on activated M1-MÏs in vitro and in vivo using differentiated bone marrow MÏs and an acute experimental model of thioglycollate-induced peritonitis, respectively. We observed that MVs-MSCs shared surface molecules with MSCs (CD44, CD105, CD90, CD73) and expressed classical microvesicle markers (Annexin V and CD9). The in vitro treatment with MVs-MSCs exerted a regulatory-like phenotype in M1-MÏs, which showed higher CD206 level and reduced CCR7 expression. This was associated with decreased levels of inflammatory molecules (IL-1ß, IL-6, nitric oxide) and increased immunoregulatory markers (IL-10 and Arginase) in M1-MÏs. In addition, we detected that MVs-MSCs promoted the downregulation of inflammatory miRNAs (miR-155 and miR-21), as well as, upregulated its predicted target gene SOCS3 in activated M1-MÏs. In vivo MVs-MSCs treatment reduced the MÏs infiltrate in the peritoneal cavity inducing a M2-like regulatory phenotype in peritoneal MÏs (higher arginase activity and reduced expression of CD86, iNOS, IFN-γ, IL-1ß, TNF-α, IL-1α, and IL-6 molecules). This in vivo immunomodulatory effect of MVs-MSCs on M1-MÏs was partially associated with the upregulation of CX3CR1 in F4/80+/Ly6C+/CCR2+ MÏs subsets. In summary, our findings indicate that MVs-MSCs can modulate an internal program in activated MÏs establishing an alternative regulatory-like phenotype.
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Oxidative stress aggravates several long-term complications in diabetes mellitus. We evaluated the effectiveness of the oral administration of antioxidants (vitamins E and C, 40 and 100 mg/kg b.w., respectively) on skin wound healing acceleration in alloxan-induced diabetic mice. Mice were wounded 30 days after the induction of diabetes. Antioxidants were effective in preventing oxidative stress, as assessed by TBARS. The enzymes catalase, glutathione reductase, glutathione peroxidase, and superoxide dismutase were increased in diabetics on the 3rd day post-wounding; catalase and glutathione peroxidase remained still augmented in diabetics after 14th day postwounding, and the treatment with vitamins restored their activities to control. After 3 days, diabetic mice showed lower infiltration of inflammatory cells (including CD11b+ and Ly6G+ cells) and reduced levels of KC, TNF-α, IL-1ß, and IL-12 p40 when compared with control mice. The treatment restored cytokine levels. After 14 days, diabetic mice showed late wound closure, persistent inflammation and delayed reepithelialization, accompanied by an increase in MIG+ /CD206- macrophages whereas CD206+ /MIG- macrophages were decreased. Cytokines IL-12p40, TNF-α, IL-1ß, and KC were increased and normal levels were restored after treatment with antioxidants. These results suggest that oxidative stress plays a major role in diabetic wound healing impairment and the oral administration of antioxidants improves healing by modulating inflammation and the antioxidant system with no effect on glycemia.
Asunto(s)
Antioxidantes/administración & dosificación , Antioxidantes/farmacología , Diabetes Mellitus Experimental/patología , Inflamación/patología , Estrés Oxidativo/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacos , Heridas y Lesiones/patología , Administración Oral , Animales , Glucemia/metabolismo , Catalasa/metabolismo , Subunidad p40 de la Interleucina-12/metabolismo , Ratones , Superóxido Dismutasa/metabolismo , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
OBJECTIVE: The interaction between nitric oxide (NO) and hydrogen sulfide (H2S) in the airways could have significant implications for the pathogenesis and therapeutic effects of both on lung diseases. In this study we investigated whether the beneficial effects of H2S on asthma could be comparable to that inhibition of inducible NO synthase (iNOS). METHODS: Female BALB/C mice sensitized with ovalbumin (OVA) received either the H2S donor sodium hydrosulfide (NaHS, 14µmol/kg) or the iNOS inhibitor 1400W (1mg/kg), 30min before each OVA challenge during six days. On the first, second and sixth days, the leucocyte infiltration in lung parenchyma and bronchoalveolar lavage was evaluated. The aconitase activity (a sensor of O2 formation) and lipid peroxidation, as well as levels of reduced glutathione (GSH) and oxidized glutathione (GSSG) were determined in the lung tissues. RESULTS: OVA-challenge caused a significant and time-dependent increase in the eosinophil number in the airways, which was accompanied by a significant decrease of aconitase activity and GSH/GSSG ratio along with enhanced lipid peroxidation in the lungs. Treatment with NaHS or 1400W significantly attenuated the airways eosinophilia that was paralleled by an increase in aconitase activity and decrease of lipid peroxidation. NaHS or 1400W treatments also reversed the decreased GSH/GSSG ratio seen after OVA-challenge. CONCLUSIONS: The present study shows for the first time that the increased GSH/GSSG ratio caused by either H2S supplementation or iNOS-inhibition is a potential mechanism protecting airways against oxidative stress and inflammatory lung diseases.
Asunto(s)
Asma/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Glutatión/metabolismo , Sulfuro de Hidrógeno/uso terapéutico , Pulmón/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Neumonía/tratamiento farmacológico , Aconitato Hidratasa/metabolismo , Animales , Movimiento Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Femenino , Pulmón/inmunología , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Neutrófilos/inmunología , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Estrés Oxidativo/efectos de los fármacosRESUMEN
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
AIMS: Calcineurin inhibitors are widely used for prevention of graft rejection and treatment of autoimmune disorders, which result in increased longevity and enhanced quality of life for patients. Unfortunately, the toxic side effects of these drugs (mainly renal, hepatic and cardiac) limit their use. In this work, we studied the effects of long-term treatment of rats with the immunosuppressant cyclosporin (CsA) or tacrolimus (Tac) on salivation, saliva composition and on the major salivary glands (parotid and submandibular) in terms of histological alterations and oxidative stress, evaluated as lipoperoxidation (thiobarbituric acid reactive species--TBARS) and antioxidant enzyme activity contents (superoxide dismutase--SOD, catalase--CAT and glutathione peroxidase--GPx). MAIN METHODS: Male adult rats were treated with either CsA (10 mg/kg/day) or Tac (1 mg/kg/day) subcutaneously for 30 or 60 days. At the end of the experimental periods, pilocarpine-stimulated salivary flow rate was measured, saliva samples were collected and the salivary glands were dissected for morphological and biochemical analyses. KEY FINDINGS: After a 60-day treatment with any of the immunosuppressants, the total protein, Ca(2+) and Na(+) saliva concentrations were decreased but salivary flow rates were unaffected. In addition, both parotid and submandibular glands showed decreased SOD, CAT and GPx activities, increased TBARS contents and histomorphological alterations involving the epithelium and acini. SIGNIFICANCE: Based on these results, we suggest that the systemic long-term administration of the calcineurin inhibitor CsA or Tac induces an impairment of the antioxidant enzymatic defense in the rat major salivary glands, which may, in turn, lead to altered saliva composition.