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The biological activities of plant-derived soluble dietary fibres (SDFs) have been widely investigated. Pectin from yellow passion fruit (YPF-peSDF) peels was suggested as a protective macromolecule in ulcers and colitis due to its antioxidant and anti-inflammatory properties. Sepsis has high mortality and morbidity and is characterised by inflammatory and oxidative stress imbalances. Evidence suggests that pectins may aid sepsis treatment; however, the effects of YPF-peSDF on sepsis remain unclear. Herein, polymicrobial sepsis was induced by cecal-ligation and puncture in mice treated with YPF-peSDF (1 and 10 mg/kg; gavage). YPF-peSDF accelerated mortality, reaching 100% in 24 h. Inflammation was present in the colons and small intestines (SI) of both vehicle- and fibre-treated mice. Although crypt depth and width, and villus height were preserved in the SI of septic mice administered YPF-peSDF, they exhibited exacerbated muscle layer atrophy and mucosa and submucosa hypertrophy, along with shortened enterocytes. Larger crypts and shorter enterocytes were noted in their colons in comparison with vehicle-controls. YPF-peSDF also reduced inflammatory cell numbers and exacerbated IL-6 levels in peritoneal lavage fluid (PELF) samples. YPF-peSDF modulated SI but not colon cytokines. Lipoperoxidation and antioxidant capacity levels were attenuated in PELF samples. Overall, in contrast to previous evidence, YPF-peSDF worsened polymicrobial sepsis outcomes in mice.
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Sepsis treatment is a challenging condition due to its complexity, which involves host inflammatory responses to a severe and potentially fatal infection, associated with organ dysfunction. The aim of this study was to analyze the scientific literature on the immunomodulatory effects of glucans in a murine model of systemic infection induced by cecal ligation and puncture. This study comprises an integrative literature review based on systematic steps, with searches carried out in the PubMed, ScienceDirect, Scopus, Web of Science, and Embase databases. In most studies, the main type of glucan investigated was ß-glucan, at 50 mg/kg, and a reduction of inflammatory responses was identified, minimizing the occurrence of tissue damage leading to increased animal survival. Based on the data obtained and discussed in this review, glucans represent a promising biotechnological alternative to modulate the immune response and could potentially be used in the clinical management of septic individuals.
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Modelos Animais de Doenças , Sepse , Animais , Sepse/tratamento farmacológico , Sepse/imunologia , Sepse/terapia , Humanos , Camundongos , Glucanos/uso terapêutico , Glucanos/farmacologia , beta-Glucanas/uso terapêutico , Imunomodulação/efeitos dos fármacosRESUMO
TRPC5 is a non-selective cation channel that is expressed in cardiomyocytes, but there is a lack of knowledge of its (patho)physiological role in vivo. Here, we examine the role of TRPC5 on cardiac function under basal conditions and during cardiac hypertrophy. Cardiovascular parameters were assessed in wild-type (WT) and global TRPC5 knockout (KO) mice. Despite no difference in blood pressure or activity, heart rate was significantly reduced in TRPC5 KO mice. Echocardiography imaging revealed an increase in stroke volume, but cardiac contractility was unaffected. The reduced heart rate persisted in isolated TRPC5 KO hearts, suggesting changes in basal cardiac pacing. Heart rate was further investigated by evaluating the reflex change following drug-induced pressure changes. The reflex bradycardic response following phenylephrine was greater in TRPC5 KO mice but the tachycardic response to SNP was unchanged, indicating an enhancement in the parasympathetic control of the heart rate. Moreover, the reduction in heart rate to carbachol was greater in isolated TRPC5 KO hearts. To evaluate the role of TRPC5 in cardiac pathology, mice were subjected to abdominal aortic banding (AAB). An exaggerated cardiac hypertrophy response to AAB was observed in TRPC5 KO mice, with an increased expression of hypertrophy markers, fibrosis, reactive oxygen species, and angiogenesis. This study provides novel evidence for a direct effect of TRPC5 on cardiac function. We propose that (1) TRPC5 is required for maintaining heart rate by regulating basal cardiac pacing and in response to pressure lowering, and (2) TRPC5 protects against pathological cardiac hypertrophy.
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Cardiomegalia , Frequência Cardíaca , Camundongos Knockout , Canais de Cátion TRPC , Animais , Canais de Cátion TRPC/metabolismo , Canais de Cátion TRPC/genética , Cardiomegalia/metabolismo , Camundongos , Masculino , Miócitos Cardíacos/metabolismo , Camundongos Endogâmicos C57BL , Pressão SanguíneaRESUMO
Sugar-induced metabolic imbalances are a major health problem since an excessive consumption of saccharides has been linked to greater obesity rates at a global level. Sucrose, a disaccharide composed of 50% glucose and 50% fructose, is commonly used in the food industry and found in a range of fast, restaurant, and processed foods. Herein, we investigated the effects of a TRPC4/TRPC5 blocker, ML204, in the metabolic imbalances triggered by early exposure to sucrose-enriched diet in mice. TRPC4 and TRPC5 belong to the family of non-selective Ca+2 channels known as transient receptor potential channels. High-sucrose (HS)-fed animals with hyperglycaemia and dyslipidaemia, were accompanied by increased body mass index. mesenteric adipose tissue accumulation with larger diameter cells and hepatic steatosis in comparison to those fed normal diet. HS mice also exhibited enhanced adipose, liver, and pancreas TNFα and VEGF levels. ML204 exacerbated hyperglycaemia, dyslipidaemia, fat tissue deposition, hepatic steatosis, and adipose tissue and liver TNFα in HS-fed mice. Normal mice treated with the blocker had greater hepatic steatosis and adipose tissue cell numbers/diameter than those receiving vehicle, but showed no significant changes in tissue inflammation, glucose, and lipid levels. The results indicate that TRPC4/TRPC5 protect against the metabolic imbalances caused by HS ingestion.
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Sepsis is an organ dysfunction syndrome associated with high mortality. To date, no effective treatment is available to combat this disease. Punica granatum L. is a potential alternative treatment due to its anti-inflammatory, antimicrobial, and antioxidant properties. Thus, this study aimed to evaluate the effects of a hydroalcoholic crude extract from the peels of P. granatum (HCEPg) in mice with lethal sepsis. Lethal polymicrobial sepsis was induced in female Swiss mice via cecal ligation and puncture (CLP). Initially, the animals were divided into three groups: Sham (false-operated), CLP-control (phosphate-buffered saline), and CLP-HCEPg (single dose, 5 mg/kg, subcutaneous administration). Treatment was initiated immediately after the induction of sepsis, and survival was evaluated every 12 hr for 5 days. Those who survived were euthanized. Serum cytokine levels were measured using a cytometric bead array Mouse Inflammatory Cytokine Kit. The number of colony-forming units, as well as the number of cells in the lymphoid organs and their activation markers, were analyzed. Results showed that treatment with HCEPg increased lifespan and reduced bacterial counts in the peritoneum, bloodstream, and spleen. HCEPg also decreased hydrogen peroxide secretion by phagocytes and augmented serum IL-10 levels, indicating its systemic anti-inflammatory effects. Additionally, treatment with HCEPg attenuated infection-induced lung hemorrhage. Overall, P. granatum extract improved the lifespan of septic mice, possibly due to its antimicrobial, anti-inflammatory, and immunomodulatory effects, thereby regulating bacterial load and translocation, as well as controlling the systemic inflammation induced by sepsis.
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Punica granatum , Sepse , Feminino , Animais , Camundongos , Longevidade , Sepse/tratamento farmacológico , Anticorpos , CitocinasRESUMO
Despite advances in the development of antimicrobial drugs in the last centuries, antimicrobial resistance has consistently raised in the last decades, compromising their effectiveness. Novel antimicrobial compounds, especially from natural sources, including plants, microorganisms, and animals, have since become a growing area of research. In this context, studies covering the investigation of their ability to combat resistant microorganisms, either by neutralization or inactivation of pathogen resistance mechanisms and virulence properties, have gained attention. Herein, a collection of 19 manuscripts focused on the antimicrobial and anti-infective activity of natural products, including their mechanisms of action, in silico evidence of antimicrobial activity, synergistic associations with antibiotics, and other aspects, will be discussed.
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Cinnamaldehyde is a natural product with anti-inflammatory and immune-modulatory properties, known to regulate host responses to bacterial stimuli. This study aimed to investigate the effects of cinnamaldehyde on ligature-induced periodontitis in rats, and its impact on the modulation of human peripheral blood mononuclear cells (PBMC). Male Wistar rats were assigned into three groups:i) control: no ligature + vehicle; ii) ligature: ligature + vehicle; and iii) ligature + cinnamaldehyde (50 mg/kg); all treatments by daily oral gavage. After 14 days of induced periodontitis, the hemimandibles were collected for bone loss evaluation. The gingival levels of IL-1ß, MMP-9 and iNOS mRNA were evaluated. Nitric oxide (NO) was measured in both rat saliva and plasma. PBMC were stimulated with Aggregatibacter actinomycetemcomitans (Aa) in the presence or absence of cinnamaldehyde (5, 20 e 40 µM), and cytokine production was quantified in cell supernatant. Proliferating lymphocytes were taken for flow cytometer reading, while culture supernatants were used for IFN-γ and IL-10 assessment. The ligature group had both increased alveolar bone loss and gingival expression of IL-1ß, MMP-9 and iNOS compared to the control group. All parameters were attenuated by cinnamaldehyde treatment. Lower salivary but not plasma NO was detected in the cinnamaldehyde compared to the ligature group. Aa-stimulated PBMCs treated with cinnamaldehyde produced less IL-1ß; the compound also attenuated lymphocyte proliferation in a dose-dependent manner, as well as cell IL-10 production. Cinnamaldehyde treatment reduced periodontal bone loss, and downregulated key inflammatory mediators and human PBMC responses, pointing to novel potential therapeutic effects of this compound.
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Perda do Osso Alveolar , Periodontite , Humanos , Ratos , Masculino , Animais , Ratos Wistar , Leucócitos Mononucleares/metabolismo , Interleucina-10/uso terapêutico , Metaloproteinase 9 da Matriz , Periodontite/metabolismo , Perda do Osso Alveolar/tratamento farmacológico , Perda do Osso Alveolar/metabolismo , Modelos Animais de DoençasRESUMO
Oropharyngeal candidiasis/candidosis is a common and recurrent opportunistic fungal infection. Fluconazole (FLZ), one of the most used and effective antifungal agents, has been associated with a rise of resistant Candida species in immunocompromised patients undergoing prophylactic therapy. Sulforaphane (SFN), a compound from cruciferous vegetables, is an antimicrobial with yet controversial activities and mechanisms on fungi. Herein, the in silico and antifungal activities of SFN against C. albicans were investigated. In silico analyzes for the prediction of the biological activities and oral bioavailability of SFN, its possible toxicity and pharmacokinetic parameters, as well as the estimates of its gastrointestinal absorption, permeability to the blood-brain barrier and skin, and similarities to drugs, were performed by using different software. SFN in vitro anti-Candida activities alone and in combination with fluconazole (FLZ) were determined by the broth microdilution method and the checkerboard, biofilm and hyphae formation tests. Amongst the identified probable biological activities of SFN, nine indicated an antimicrobial potential. SFN was predicted to be highly absorbable by the gastrointestinal tract, to present good oral availability, and not to be irritant and/or hepatotoxic. SFN presented antifungal activity against C. albicans and prevented both biofilm and hyphae formation by this microorganism. SFN was additive/synergistic to FLZ. Overall, the data highlights the anti-Candida activity of SFN and its potential to be used as an adjuvant therapy to FLZ in clinical settings.
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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 Metabólica , Canais de Potencial de Receptor Transitório , Animais , Inflamação , Síndrome Metabólica/terapia , Estresse Oxidativo , Termogênese , Canais de Potencial de Receptor Transitório/metabolismoRESUMO
Limosilactobacillus fermentum (ATCC 23271) was originally isolated from the human intestine and has displayed antimicrobial activity, primarily against Candida species. Complete genome sequencing and comparative analyses were performed to elucidate the genetic basis underlying its probiotic potential. The ATCC 23271 genome was found to contain 2,193,335 bp, with 2123 protein-coding sequences. Phylogenetic analysis revealed that the ATCC 23271 strain shares 941 gene clusters with six other probiotic strains of L. fermentum. Putative genes known to confer probiotic properties have been identified in the genome, including genes related to adhesion, tolerance to acidic pH and bile salts, tolerance to oxidative stress, and metabolism and transport of sugars and other compounds. A search for bacteriocin genes revealed a sequence 48% similar to that of enterolysin A, a protein from Enterococcus faecalis. However, in vitro assays confirmed that the strain has inhibitory activity on the growth of Candida species and also interferes with their adhesion to HeLa cells. In silico analyses demonstrated a high probability of the protein with antimicrobial activity. Our data reveal the genome features of L. fermentum ATCC 23271, which may provide insight into its future use given the functional benefits, especially against Candida infections.
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Rheumatoid arthritis (RA) is a painful inflammatory disease of the joints which affects a considerable proportion of the world population, mostly women. If not adequately treated, RA patients can become permanently disabled. Importantly, not all the patients respond to the available anti-rheumatic therapies, which also present diverse side effects. In this context, monitoring of treatment response is pivotal to avoid unnecessary side effects and costs towards an ineffective therapy. Herein, we performed a pilot study to investigate the potential use of flow cytometry and attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy as measures to identify responders and non-responders to leflunomide, a disease-modifying drug used in the treatment of RA patients. The evaluation of peripheral blood CD62L+ polymorphonuclear cell numbers and ATR-FTIR vibrational modes in plasma were able to discriminate responders to leflunomide (LFN) three-months after therapy has started. Overall, the results indicate that both flow cytometry and ATR-FTIR can potentially be employed as additional measures to monitor early treatment response to LFN in RA patients.
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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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Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Hemoglobinas/farmacologia , Dor Nociceptiva/prevenção & controle , Fragmentos de Peptídeos/farmacologia , Administração Oral , Animais , Anti-Inflamatórios/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Citocinas/metabolismo , Edema/tratamento farmacológico , Marcha/efeitos dos fármacos , Hemoglobinas/administração & dosagem , Inflamação/tratamento farmacológico , Injeções Intra-Articulares , Articulação do Joelho/efeitos dos fármacos , Articulação do Joelho/metabolismo , Articulação do Joelho/patologia , Leucócitos/efeitos dos fármacos , Masculino , Fragmentos de Peptídeos/administração & dosagem , Ratos Sprague-Dawley , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Substância P/metabolismoRESUMO
Escherichia coli and Staphylococcus aureus are important agents of urinary tract infections that can often evolve to severe infections. The rise of antibiotic-resistant strains has driven the search for novel therapies to replace the use or act as adjuvants of antibiotics. In this context, plant-derived compounds have been widely investigated. Cuminaldehyde is suggested as the major antimicrobial compound of the cumin seed essential oil. However, this effect is not fully understood. Herein, we investigated the in silico and in vitro activities of cuminaldehyde, as well as its ability to potentiate ciprofloxacin effects against S. aureus and E. coli. In silico analyses were performed by using different computational tools. The PASS online and SwissADME programmes were used for the prediction of biological activities and oral bioavailability of cuminaldehyde. For analysis of the possible toxic effects and the theoretical pharmacokinetic parameters of the compound, the Osiris, SwissADME and PROTOX programmes were used. Estimations of cuminaldehyde gastrointestinal absorption, blood brain barrier permeability and skin permeation by using SwissADME; and drug likeness and score by using Osiris, were also evaluated The in vitro antimicrobial effects of cuminaldehyde were determined by using microdilution, biofilm formation and time-kill assays. In silico analysis indicated that cuminaldehyde may act as an antimicrobial and as a membrane permeability enhancer. It was suggested to be highly absorbable by the gastrointestinal tract and likely to cross the blood brain barrier. Also, irritative and harmful effects were predicted for cuminaldehyde if swallowed at its LD50. Good oral bioavailability and drug score were also found for this compound. Cuminaldehyde presented antimicrobial and anti-biofilm effects against S. aureus and E. coli.. When co-incubated with ciprofloxacin, it enhanced the antibiotic antimicrobial and anti-biofilm actions. We suggest that cuminaldehyde may be useful as an adjuvant therapy to ciprofloxacin in S. aureus and E. coli-induced infections.
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Antibacterianos/administração & dosagem , Benzaldeídos/administração & dosagem , Ciprofloxacina/administração & dosagem , Cimenos/administração & dosagem , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Adjuvantes Farmacêuticos/administração & dosagem , Adjuvantes Farmacêuticos/farmacocinética , Adjuvantes Farmacêuticos/toxicidade , Administração Oral , Benzaldeídos/farmacocinética , Benzaldeídos/toxicidade , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Disponibilidade Biológica , Simulação por Computador , Cimenos/farmacocinética , Cimenos/toxicidade , Sinergismo Farmacológico , Escherichia coli/patogenicidade , Escherichia coli/fisiologia , Infecções por Escherichia coli/tratamento farmacológico , Humanos , Técnicas In Vitro , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/patogenicidade , Staphylococcus aureus/fisiologia , Infecções Urinárias/tratamento farmacológicoRESUMO
Taxane-derived drugs are antineoplastic agents used for the treatment of highly common malignancies. Paclitaxel and docetaxel are the most commonly used taxanes; however, other drugs and formulations have been used, such as cabazitaxel and nab-paclitaxel. Taxane treatment is associated with neurotoxicity, a well-known and relevant side effect, very prevalent amongst patients undergoing chemotherapy. Painful peripheral neuropathy is the most dose-limiting side effect of taxanes, affecting up to 97% of paclitaxel-treated patients. Central neurotoxicity is an emerging side effect of taxanes and it is characterized by cognitive impairment and encephalopathy. Besides impairing compliance to chemotherapy treatment, taxane-induced neurotoxicity (TIN) can adversely affect the patient's life quality on a long-term basis. Despite the clinical relevance, not many reviews have comprehensively addressed taxane-induced neurotoxicity when they are used therapeutically. This article provides an up-to-date review on the pathophysiology of TIN and the novel potential therapies to prevent or treat this side effect.
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Antineoplásicos , Taxoides , Antineoplásicos/efeitos adversos , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Docetaxel , Humanos , Paclitaxel , Taxoides/efeitos adversosRESUMO
Phosphodiesterases (PDEs) form a superfamily of enzymes that catalyze the hydrolysis of cyclic nucleotides adenosine 3'5'-cyclic monophosphate (cAMP) and guanosine 3'5'-cyclic monophosphate (cGMP) to their inactive 5' monophosphates. cAMP plays a critical role as a second messenger in endocrine tissues, and activation of cAMP signaling has been reported in endocrine tumors. Germline variants in PDEs have been associated with benign cortisol-secreting adrenocortical adenomas and testicular germ cell cancer but not adrenocortical carcinoma. We performed whole genome sequencing (WGS) and whole exome sequencing (WES) of paired blood and tumor samples from 37 pediatric adrenocortical tumors (ACTs). Germline inactivating variants in PDEs were observed in 9 of 37 (24%) patients. Tumor DNA analysis revealed loss of heterozygosity, with maintenance of the mutated allele in all cases. Our results suggest that germline variants in PDEs and other regulators of the cAMP-signaling pathway may contribute to pediatric adrenocortical tumorigenesis, perhaps by cooperating with germline hypomorphic mutant TP53 alleles and uniparental disomy of chromosome 11p15 (Beckwith-Wiedemann syndrome).
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[This corrects the article DOI: 10.3389/fmicb.2016.02052.].
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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-1β, 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-1β, 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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Painful peripheral neuropathy is the most dose-limiting side effect of paclitaxel (PTX), a widely used anti-cancer drug to treat solid tumours. The understanding of the mechanisms involved in this side effect is crucial to the development of new therapeutic approaches. CXCL1 chemokine and its receptor CXCR2 have been pointed as promising targets to treat chronic pain. Herein, we sought to evaluate the possible involvement of CXCL1 and CXCR2 in the pathogenesis of PTX-induced neuropathic pain in mice. PTX treatment led to increased levels of CXCL1 in both dorsal root ganglion and spinal cord samples. Systemic treatment with the anti-CXCL1 antibody (10⯵g/kg, i.v.) or the selective CXCR2 antagonist (SB225002, 3â¯mg/kg, i.p.) had minor effect on PTX-induced mechanical hypersensitivity. On the other hand, the intrathecal (i.t.) treatment with anti-CXCL1 (1 ng/site) or SB225002 (10 µg/site) consistently inhibited the nociceptive responses of PTX-treated mice. Similar results were obtained by inhibiting the PI3Kγ enzyme a downstream pathway of CXCL1/CXCR2 signalling with either the selective AS605240 (5 µg/site, i.t.) or the non-selective wortmannin PI3K inhibitor (0.4 µg/site, i.t.). Overall, the data indicates that the up-regulation of CXCL1 is important for the development and maintenance of PTX-induced neuropathic pain in mice. Therefore, the spinal blockage of CXCL1/CXCR2 signalling might be a new innovative therapeutic approach to treat this clinical side effect of PTX.
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Antineoplásicos Fitogênicos/efeitos adversos , Quimiocina CXCL1/antagonistas & inibidores , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Receptores de Interleucina-8B/antagonistas & inibidores , Medula Espinal/efeitos dos fármacos , Animais , Quimiocina CXCL1/metabolismo , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Compostos de Fenilureia/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Quinoxalinas/farmacologia , Receptores de Interleucina-8B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/metabolismo , Tiazolidinedionas/farmacologiaRESUMO
Wound healing can be delayed following colonization and infection with the common bacterium Pseudomonas aeruginosa. While multiple therapies are used for their treatment, these are ineffective, expensive, and labour-intensive. Thus, there is an enormous unmet need for the treatment of infected wounds. Cinnamaldehyde, the major component of cinnamon oil, is well known for its antimicrobial properties. Herein, we investigated the effects of sub-inhibitory concentrations of cinnamaldehyde in the virulence of P. aeruginosa. We also assessed its healing potential in P. aeruginosa-infected mouse skin wounds and the mechanisms involved in this response. Sub-inhibitory concentrations of cinnamaldehyde reduced P. aeruginosa metabolic rate and its ability to form biofilm and to cause haemolysis. Daily topical application of cinnamaldehyde on P. aeruginosa-infected skin wounds reduced tissue bacterial load and promoted faster healing. Lower interleukin-17 (IL-17), vascular endothelial growth factor (VEGF) and nitric oxide levels were detected in cinnamaldehyde-treated wound samples. Blockage of transient receptor potential ankyrin 1, the pharmacological target of cinnamaldehyde, abrogated its healing activity and partially reversed the inhibitory actions of this compound on VEGF and IL-17 generation. We suggest that topical application of sub-inhibitory concentrations of cinnamaldehyde may represent an interesting approach to improve the healing of P. aeruginosa-infected skin wounds.
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Acroleína/análogos & derivados , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/patogenicidade , Pele/microbiologia , Cicatrização/efeitos dos fármacos , Acroleína/uso terapêutico , Animais , Anti-Infecciosos/uso terapêutico , Biofilmes/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Interleucina-17/metabolismo , Camundongos , Infecções por Pseudomonas/tratamento farmacológico , Canal de Cátion TRPA1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
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.