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Intense exposure to UVB radiation incites excessive production of reactive oxygen species (ROS) and inflammation. The resolution of inflammation is an active process orchestrated by a family of lipid molecules that includes AT-RvD1, a specialized proresolving lipid mediator (SPM). AT-RvD1 is derived from omega-3, which presents anti-inflammatory activity and reduces oxidative stress markers. The present work aims to investigate the protective effect of AT-RvD1 on UVB-induced inflammation and oxidative stress in hairless mice. Animals were first treated with 30, 100, and 300 pg/animal AT-RvD1 (i.v.) and then exposed to UVB (4.14 J/cm2). The results showed that 300 pg/animal of AT-RvD1 could restrict skin edema, neutrophil and mast cell infiltration, COX-2 mRNA expression, cytokine release, and MMP-9 activity and restore skin antioxidant capacity as per FRAP and ABTS assays and control O2â¢- production, lipoperoxidation, epidermal thickening, and sunburn cells development. AT-RvD1 could reverse the UVB-induced downregulation of Nrf2 and its downstream targets GSH, catalase, and NOQ-1. Our results suggest that by upregulating the Nrf2 pathway, AT-RvD1 promotes the expression of ARE genes, restoring the skin's natural antioxidant defense against UVB exposition to avoid oxidative stress, inflammation, and tissue damage.
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Antioxidantes , Aspirina , Animais , Camundongos , Antioxidantes/farmacologia , Aspirina/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Inflamação , Ácidos Docosa-Hexaenoicos/farmacologia , Raios UltravioletaRESUMO
BACKGROUND: Despite the wide variety of Covid-19 symptoms, pain and the related mechanisms underlying unsettled nociceptive status are still under-prioritized. Understanding the complex network of Covid-19-related pain may result in new lines of study. It is unknown whether patient's immunological background influences pain in the acute phase of Covid-19, including musculoskeletal pain. Thus, we evaluated the blood levels of selected molecules that are upregulated in SARS-CoV-2 infection and analyzed a possible correlation with pain during Covid-19. METHODS: A cohort of 20 hospitalized patients with confirmed diagnoses for Covid-19 were evaluated in the context of pain. Visual analogic scale (VAS) was applied to quantitate pain level. Blood tests were used to determine the systemic levels of cytokines (IL-10 and IL-1ß), substance P, and leptin. The data were correlated when appropriate to determine the association between pain-related markers and assessed pain intensity. RESULTS: Our findings show that systemic levels of IL-10 have strong negative correlation with pain intensity on Covid-19 patients. Additionally, we also show that leptin systemic levels were increased in Covid-19 patients with pain, however, with moderate positive correlation between these events. IL-1ß and SP levels did not differ between Covid-19 patients with or without pain. Men reported less pain compared to women. No differences were found between genders in the levels of the molecules evaluated in patients with pain. CONCLUSION: IL-10 has been described over the years as an anti-inflammatory and analgesic cytokine. The present data support that low IL-10 levels might contribute to Covid-19-associated pain.
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COVID-19 , Interleucina-10/sangue , COVID-19/complicações , Citocinas , Feminino , Humanos , Leptina , Masculino , Dor , SARS-CoV-2RESUMO
Excessive exposure to UV, especially UVB, is the most important risk factor for skin cancer and premature skin aging. The identification of the specialized pro-resolving lipid mediators (SPMs) challenged the preexisting paradigm of how inflammation ends. Rather than a passive process, the resolution of inflammation relies on the active production of SPMs, such as Lipoxins (Lx), Maresins, protectins, and Resolvins. LXA4 is an SPM that exerts its action through ALX/FPR2 receptor. Stable ALX/FPR2 agonists are required because SPMs can be quickly metabolized within tissues near the site of formation. BML-111 is a commercially available synthetic ALX/FPR2 receptor agonist with analgesic, antioxidant, and anti-inflammatory properties. Based on that, we aimed to determine the effect of BML-111 in a model of UVB-induced skin inflammation in hairless mice. We demonstrated that BML-111 ameliorates the signs of UVB-induced skin inflammation by reducing neutrophil recruitment and mast cell activation. Reduction of these cells by BML-111 led to lower number of sunburn cells formation, decrease in epidermal thickness, collagen degradation, cytokine production (TNF-α, IL-1ß, IL-6, TGF, and IL-10), and oxidative stress (observed by an increase in total antioxidant capacity and Nrf2 signaling pathway), indicating that BML-111 might be a promising drug to treat skin disorders.
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Dermatite/prevenção & controle , Ácidos Heptanoicos/administração & dosagem , Protetores contra Radiação/administração & dosagem , Receptores de Lipoxinas/antagonistas & inibidores , Animais , Antígenos CD59/metabolismo , Dermatite/etiologia , Dermatite/metabolismo , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/metabolismo , Relação Dose-Resposta a Droga , Ácidos Heptanoicos/farmacologia , Lipoxinas/metabolismo , Camundongos , Camundongos Pelados , Protetores contra Radiação/farmacologia , Raios Ultravioleta/efeitos adversosRESUMO
BACKGROUND: Naringenin is a biologically active analgesic, anti-inflammatory, and antioxidant flavonoid. Naringenin targets in inflammation-induced articular pain remain poorly explored. METHODS: The present study investigated the cellular and molecular mechanisms involved in the analgesic/anti-inflammatory effects of naringenin in zymosan-induced arthritis. Mice were pre-treated orally with naringenin (16.7-150 mg/kg), followed by intra-articular injection of zymosan. Articular mechanical hyperalgesia and oedema, leucocyte recruitment to synovial cavity, histopathology, expression/production of pro- and anti-inflammatory mediators and NFκB activation, inflammasome component expression, and oxidative stress were evaluated. RESULTS: Naringenin inhibited articular pain and oedema in a dose-dependent manner. The dose of 50 mg/kg inhibited leucocyte recruitment, histopathological alterations, NFκB activation, and NFκB-dependent pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-33), and preproET-1 mRNA expression, but increased anti-inflammatory IL-10. Naringenin also inhibited inflammasome upregulation (reduced Nlrp3, ASC, caspase-1, and pro-IL-1ß mRNA expression) and oxidative stress (reduced gp91phox mRNA expression and superoxide anion production, increased GSH levels, induced Nrf2 protein in CD45+ hematopoietic recruited cells, and induced Nrf2 and HO-1 mRNA expression). CONCLUSIONS: Naringenin presents analgesic and anti-inflammatory effects in zymosan-induced arthritis by targeting its main physiopathological mechanisms. These data highlight this flavonoid as an interesting therapeutic compound to treat joint inflammation, deserving additional pre-clinical and clinical studies.
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Artrite/tratamento farmacológico , Flavanonas/uso terapêutico , Antígenos Comuns de Leucócito/análise , Fator 2 Relacionado a NF-E2/fisiologia , Zimosan/farmacologia , Animais , Citocinas/biossíntese , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Flavanonas/farmacologia , Células-Tronco Hematopoéticas/metabolismo , Inflamassomos/efeitos dos fármacos , Articulação do Joelho/patologia , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de SinaisRESUMO
INTRODUCTION: Post-sepsis cognitive impairment is one of the major sequelae observed in survivors of sepsis. This cognitive impairment can be global or may affect specific domains. A better understanding of these deficits and associated risk factors could influence the care of patients with sepsis. OBJECTIVE: To perform a systematic review to investigate the presence of cognitive impairment and its associated risk factors among patients who survived sepsis. METHODS: The search was conducted in MEDLINE (1966 to March 2017) and EMBASE (1988 to March 2017). We included studies with individuals who were 18 years or older with post-sepsis cognitive impairment. RESULTS: We analysed 577 articles. Sixteen studies met the inclusion criteria. More than 74,000,000 patients were evaluated in the selected studies. Significant variation was observed in the definition of sepsis and cognitive impairment. Twelve studies used ACCP/SCCM criteria for sepsis, while cognitive impairment was defined per test used. Post-sepsis cognitive impairment was observed in 12.5 to 21% of survivors of sepsis. Attention, cognitive flexibility, processing speed, associative learning, visual perception, work memory, verbal memory, and semantic memory were the specific domains affected. Depressive symptoms, central nervous system infection, length of hospitalisation due to infection, and temporal proximity to the last period of infection were associated with cognitive impairment. CONCLUSION: The studies are heterogeneous, and there is urgent need for a common language, including definitions and neuropsychological tests, for the investigation of post-sepsis cognitive impairment. Despite this, there is mounting evidence for the clinical relevance of post-sepsis cognitive impairment. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017054583 (www.crd.york.ac.uk/PROSPERO).
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Disfunção Cognitiva/etiologia , Sepse/complicações , Humanos , Testes Neuropsicológicos , Fatores de RiscoRESUMO
Acute kidney injury (AKI) represents a complex clinical condition associated with significant morbidity and mortality. Approximately, 19-33% AKI episodes in hospitalized patients are related to drug-induced nephrotoxicity. Although, considered safe, non-steroidal anti-inflammatory drugs such as diclofenac have received special attention in the past years due to the potential risk of renal damage. Vinpocetine is a nootropic drug known to have anti-inflammatory properties. In this study, we investigated the effect and mechanisms of vinpocetine in a model of diclofenac-induced AKI. We observed that diclofenac increased proteinuria and blood urea, creatinine, and oxidative stress levels 24h after its administration. In renal tissue, diclofenac also increased oxidative stress and induced morphological changes consistent with renal damage. Moreover, diclofenac induced kidney cells apoptosis, up-regulated proinflammatory cytokines, and induced the activation of NF-κB in renal tissue. On the other hand, vinpocetine reduced diclofenac-induced blood urea and creatinine. In the kidneys, vinpocetine inhibited diclofenac-induced oxidative stress, morphological changes, apoptosis, cytokine production, and NF-κB activation. To our knowledge, this is the first study demonstrating that diclofenac-induced AKI increases NF-κB activation, and that vinpocetine reduces the nephrotoxic effects of diclofenac. Therefore, vinpocetine is a promising molecule for the treatment of diclofenac-induced AKI.
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Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Anti-Inflamatórios não Esteroides/efeitos adversos , Diclofenaco/efeitos adversos , Rim/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Substâncias Protetoras/uso terapêutico , Alcaloides de Vinca/uso terapêutico , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Citocinas/imunologia , Rim/imunologia , Rim/patologia , Masculino , Camundongos , NF-kappa B/imunologia , Nootrópicos/uso terapêutico , Estresse Oxidativo/efeitos dos fármacosRESUMO
trans-Chalcone is a plant flavonoid precursor, which lacks broad investigation on its biological activity in inflammatory processes. In the present study, anti-inflammatory and antioxidant mechanisms of systemic administration with trans-chalcone, a flavonoid precursor, on ultraviolet (UV) irradiation-induced skin inflammation and oxidative stress in hairless mice were investigated by the following parameters: skin edema, myeloperoxidase activity (neutrophil marker), matrix metalloproteinase-9 activity, reduced glutathione levels, catalase activity, lipid peroxidation products, superoxide anion production, gp91phox (NADPH oxidase subunit) mRNA expression by quantitative PCR and cytokine production by ELISA. Systemic treatment with trans-chalcone inhibited skin inflammation by reducing skin edema and neutrophil recruitment, and also inhibited matrix metalloproteinase-9 activity. trans-Chalcone also inhibited oxidative stress, gp91phox mRNA expression, and the production of a wide range of pro-inflammatory cytokines, while it did not affect anti-inflammatory cytokines induced by UV irradiation. However, trans-chalcone did not prevent oxidative stress in vitro, suggesting that its in vivo effect is more related to anti-inflammatory properties rather than a direct antioxidant effect. In conclusion, treatment with trans-chalcone inhibited UV-induced skin inflammation resulting in oxidative stress inhibition in vivo. Therefore, systemic supplementation with this compound may represent an important therapeutic approach in inflammatory skin diseases induced by UV irradiation.
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Chalcona/farmacologia , Citocinas/biossíntese , Inflamação/prevenção & controle , NADPH Oxidases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Raios Ultravioleta , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Chalcona/química , Relação Dose-Resposta a Droga , Edema/tratamento farmacológico , Ensaio de Imunoadsorção Enzimática , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Pelados , Estrutura Molecular , Estresse Oxidativo/efeitos da radiação , Pele/metabolismo , Pele/patologia , Relação Estrutura-AtividadeRESUMO
In this present study, carried out between November 2020 and July 2023 at Londrina's University Hospital, patients with active lesions of cutaneous leishmaniasis (CL) were analyzed regarding pain perception and anatomopathological aspects of the ulcers. Pain was assessed using a numerical rating scale (NRS) to compare five patients diagnosed with CL with four control patients diagnosed with vascular skin ulcers. Histopathological evaluations were used to investigate the nociceptor neuron-Leishmania interface. Patients with CL ulcers reported less pain compared to patients with vascular ulcers (2.60 ± 2.30 and 7.25 ± 0.95, respectively, p = 0.0072). Histopathology evidenced Leishmania spp. amastigote forms nearby sensory nerve fibers in profound dermis. Schwann cells marker (S100 protein) was detected, and caspase-3 activation was not evidenced in the in the nerve fibers of CL patients' samples, suggesting absence of apoptotic activity in nerve endings. Additionally, samples taken from the active edge of the lesion were negative for bacilli acid-alcohol resistant (BAAR), which excludes concomitant leprosy, in which painless lesions are also observed. Thus, the present data unveil for the first time anatomopathological and microbiological details of painless ulcers in CL patients, which has important clinical implications for a better understanding on the intriguing painless clinical characteristic of CL.
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Apoptose , Leishmania , Leishmaniose Cutânea , Úlcera Cutânea , Humanos , Masculino , Feminino , Leishmaniose Cutânea/patologia , Leishmaniose Cutânea/parasitologia , Adulto , Pessoa de Meia-Idade , Úlcera Cutânea/parasitologia , Úlcera Cutânea/patologia , Células Receptoras Sensoriais/patologia , Neurônios/patologia , Idoso , Pele/parasitologia , Pele/patologia , Pele/inervaçãoRESUMO
While studying the detailed anatomy of the cranial sella turcica, an additional fossa in its floor, which has not previously been described, was noted. A survey for this fossa, therefore, was conducted on 205 adult crania from the Raymond A. Dart Collection of Human Skeletons, University of the Witwatersrand. To confirm the survey observations, the sella turcica region of 10 adult cadavers was also dissected. A larger anterior depression and a smaller posterior concave fossa, often extending on to the anterior surface of the dorsum sellae, were evident in the hypophysial region and occurred in 21.5% of crania and in six of the 10 dissected specimens. An anterior depression alone or a posterior fossa alone occurred in 2.4% and in 72% of the crania, respectively, indicating that the posterior fossa occurs most commonly in this series. The more commonly occurring presence of a posterior fossa abutting on to the anterior surface of the dorsum sellae is described for the first time.
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Hipófise/anatomia & histologia , Sela Túrcica/anatomia & histologia , Adulto , Cadáver , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Sphagneticola trilobata (L.) Pruski is used in traditional medicine in Brazil for inflammatory diseases treatment including asthma. The diterpene kaurenoic acid (KA) is one of its active compounds, but whether KA activity could explain the traditional use of S. trilobata in asthma is unknown. AIM: Investigate KA effect and mechanisms in asthma. METHODS: Experimental asthma was induced by ovalbumin immunization and challenge in male Swiss mice. KA (0.1-10 mg/kg, gavage) was administered 1 h before the ovalbumin challenge. Total leukocytes, eosinophil, and mast cell were counted in bronchoalveolar lavage fluid (BALF), and lung histopathology was performed. Lung mRNA expression of Th2 and regulatory T cells markers, and BALF type 2 cytokine production were quantitated. NFκB activation and oxidative stress-related components in pulmonary tissue were measured. RESULTS: KA inhibited the migration of total leukocytes and eosinophils to BALF, reduced lung histopathology (inflammatory cells and mast cells), mRNA expression of IL-33/ST2, STAT6/GATA-3 and NFκB activation in the lung, and reduced IL-33, IL-4, IL-5 production in the BALF. KA also reduced the mRNA expression of iNOS and gp91phox, and superoxide anion production accompanied by the induction of Nrf2, HO-1 and NQO1 mRNA expression, thus, exerting an antioxidant effect. Finally, KA induced nTreg-like and Tr1-like, but not Th3-like markers of suppressive T cell phenotypes in the lung tissue. CONCLUSION: KA prevents antigen-induced asthma by down-regulating Th2 and NFκB/cytokine-related pathways, and up-regulating Nrf2 and regulatory T cells' markers. Thus, explaining the ethnopharmacological use of S. trilobata for the treatment of lung inflammatory diseases.
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Asteraceae/química , Asma/tratamento farmacológico , Citocinas/metabolismo , Diterpenos/farmacologia , Animais , Modelos Animais de Doenças , Diterpenos/administração & dosagem , Diterpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Fator de Transcrição GATA3/metabolismo , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Ovalbumina/imunologia , Fator de Transcrição STAT6/metabolismo , Células Th2/imunologiaRESUMO
Hesperidin is derived from citrus fruits among other plants. Hesperidin was methylated to increase its solubility, generating hesperidin methyl chalcone (HMC), an emerging flavonoid that possess anti-inflammatory and antioxidant properties. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a powerful regulator of cellular resistance to oxidant products. Previous data evidenced HMC can activate Nrf2 signaling, providing antioxidant protection against diverse pathological conditions. However, its effects on kidney damage caused by non-steroidal anti-inflammatory drugs (NSAIDs) have not been evaluated so far. Mice received a nephrotoxic dose of diclofenac (200 mg/kg) orally followed by intra-peritoneal (i.p.) administration of HMC (0.03-3 mg/kg) or vehicle. Plasmatic levels of urea, creatinine, oxidative stress, and cytokines were assessed. Regarding the kidneys, oxidative parameters, cytokine production, kidney swelling, urine NGAL, histopathology, and Nrf2 mRNA expression and downstream targets were evaluated. HMC dose-dependently targeted diclofenac systemic alterations by decreasing urea and creatinine levels, and lipid peroxidation, as well as IL-6, IFN-γ, and IL-33 production, and restored antioxidant properties in plasma samples. In kidney samples, HMC re-established antioxidant defenses, inhibited lipid peroxidation and pro-inflammatory cytokines and upregulated IL-10, reduced kidney swelling, urine NGAL, and histopathological alterations. Additionally, HMC induced mRNA expression of Nrf2 and its downstream effectors HO-1 and Nqo1, as well as reduced the levels of Keap1 protein detected in renal tissue. The present data demonstrate HMC is a potential compound for the treatment of acute renal damage caused by diclofenac, a routinely prescribed non-steroidal anti-inflammatory drug.
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Acetaminophen (paracetamol) is a widely used analgesic and antipyretic drug that is safe at therapeutic doses. However, acetaminophen overdose can be fatal. Currently, the only treatment available is the N-acetyl cysteine. The diterpene kaurenoic acid (ent-kaur-16-en-19-oic acid, KA) is the major constituent of Sphagneticola trilobata (L.) Pruski. KA presents anti-inflammatory, anti-nociceptive and antioxidant properties. In this study, we evaluated the efficacy of KA in a model of acetaminophen-induced hepatotoxicity. KA increased, in a dose-dependent manner, the survival rate after acetaminophen overdose. KA reduced acetaminophen-induced hepatic necrosis and ALT and AST levels. KA decreased acetaminophen-induced neutrophil and macrophage recruitment, oxidative stress and the production of IL-33, TNF-α and IL-1ß, alongside with normalisation of IL-10 levels in the liver. Therefore, KA showed preclinical efficacy in acetaminophen-induced hepatotoxicity and lethality.
Assuntos
Acetaminofen/toxicidade , Asteraceae/química , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Diterpenos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Brasil , Diterpenos/isolamento & purificação , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucina-33/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Raízes de Plantas/química , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Monosodium urate crystals (MSU) deposition induces articular inflammation known as gout. This disease is characterized by intense articular inflammation and pain by mechanisms involving the activation of the transcription factor NFκB and inflammasome resulting in the production of cytokines and oxidative stress. Despite evidence that MSU induces iNOS expression, there is no evidence on the effect of nitric oxide (NO) donors in gout. Thus, the present study evaluated the effect of the ruthenium complex donor of NO {[Ru(bpy)2(NO)SO3](PF6)} (complex I) in gout arthritis. Complex I inhibited in a dose-dependent manner MSU-induced hypersensitivity to mechanical stimulation, edema and leukocyte recruitment. These effects were corroborated by a decrease of histological inflammation score and recruitment of Lysm-eGFP+ cells. Mechanistically, complex I inhibited MSU-induced mechanical hypersensitivity and joint edema by triggering the cGMP/PKG/ATP-sensitive K (+) channels signaling pathway. Complex I inhibited MSU-induced oxidative stress and pro-inflammatory cytokine production in the knee joint. These data were supported by the observation that complex I inhibited MSU-induced NFκB activation, and IL-1ß expression and production. Complex I also inhibited MSU-induced activation of pro-IL-1ß processing. Concluding, the present data, to our knowledge, is the first evidence that a NO donating ruthenium complex inhibits MSU-induced articular inflammation and pain. Further, complex I targets the main physiopathological mechanisms of gout arthritis. Therefore, it is envisaged that complex I and other NO donors have therapeutic potential that deserves further investigation.
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This study aimed to assess cognition in patients with severe sepsis or septic shock and whether cognitive impairment was associated with clinical and laboratory parameters. We conducted a cohort study of patients with severe sepsis and septic shock evaluated within 24 h and one year after ICU discharge. Demographic, clinical and laboratory data were analyzed, and the following neuropsychological tests were applied: Consortium to Establish Registry for Alzheimer's Disease, Mini-Mental State Examination, and Trail Making Test forms A and B. We included 33 patients, mean age of 49, 19% were female. Patients underperformed on most measures 24 h after ICU discharge, with improvement on follow-up. IQCODE, APACHE II scores, NSE and IFN-γ levels at ICU discharge were associated with poor cognitive performance, while higher educational level was associated with good cognitive performance. The time to first antibiotic dose, accumulated dose of haloperidol during UCI stay and mean glycemia were also associated with poor cognitive outcome. In general, patients with severe sepsis or septic shock have cognitive impairment that can improve over time. This improvement was associated with factors identified during their ICU stay, such as cognitive reserve, educational level, mean glycemia during ICU stay and NSE level.
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Cognição , Disfunção Cognitiva/psicologia , Sepse/psicologia , Adulto , Biomarcadores , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Citocinas/sangue , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sepse/complicações , Sepse/diagnóstico , Sepse/etiologia , Índice de Gravidade de Doença , Choque Séptico/complicações , Choque Séptico/diagnóstico , Choque Séptico/etiologia , Choque Séptico/psicologia , Fatores de TempoRESUMO
AIMS: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used and effective anti-inflammatories despite the well-known side effects such as gastrointestinal damage, acute kidney injury (AKI), and cardiovascular dysfunctions. Diclofenac is among the most prescribed NSAIDs due to its efficient analgesic and anti-inflammatory properties. Patients using diclofenac possess 77% risk increase to develop AKI. Activation of NF-κB contributes to diclofenac-induced AKI, which is in line with the use of glucocorticoids as one of the management choices to treat AKI patients. MAIN METHODS: In this work, we investigate the efficacy of pyrrolidine dithiocarbamate (PDTC) in diclofenac-induced AKI in mice given it is a known NF-κB inhibitor. KEY FINDINGS: We observed that diclofenac increased proteinuria and urine neutrophil gelatinase-associated lipocalin (NGAL), blood levels of urea, creatinine, oxidative stress, C-reactive protein (CRP), and pro-inflammatory cytokine after 24â¯h of a bolus administration. In renal tissue, diclofenac also induced morphological changes consistent with kidney damage, modulated cytokine production, increased oxidative stress and reduced antioxidant defenses. These alterations induced by diclofenac were accompanied by activation of NF-κB in the kidney. Treatment with PDTC dose-dependently reduced diclofenac-induced blood urea, creatinine, and oxidative stress. In addition, PDTC reduced proteinuria and urine NGAL levels and blood CRP and pro-inflammatory cytokines. In the kidney, PDTC inhibited diclofenac-induced morphological changes, pro-inflammatory cytokine production, oxidative stress, and NF-κB activation, and increased antioxidant defenses and anti-inflammatory cytokine IL-10. SIGNIFICANCE: Our data demonstrate that PDTC ameliorates diclofenac-induced AKI and that targeting NF-κB signaling pathway is a promising therapeutic approach for the treatment of diclofenac-induced AKI.
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Injúria Renal Aguda/prevenção & controle , Antioxidantes/farmacologia , Citocinas/metabolismo , Diclofenaco/toxicidade , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pirrolidinas/farmacologia , Tiocarbamatos/farmacologia , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , Anti-Inflamatórios não Esteroides/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , NF-kappa B/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
UV irradiation-induced oxidative stress and inflammation contribute to the development of skin diseases. Therefore, targeting oxidative stress and inflammation might contribute to reduce skin diseases. Resolvin D1 (RvD1) is a bioactive metabolite generated during inflammation to actively orchestrate the resolution of inflammation. However, the therapeutic potential of RvD1 in UVB skin inflammation remains undetermined, which was, therefore, the aim of the present study. The intraperitoneal treatment with RvD1 (3-100 ng/mouse) reduced UVB irradiation-induced skin edema, myeloperoxidase activity, matrix metalloproteinase 9 activity, and reduced glutathione depletion with consistent effects observed with the dose of 30 ng/mouse, which was selected to the following experiments. RvD1 inhibited UVB reduction of catalase activity, and hydroperoxide formation, superoxide anion production, and gp91phox mRNA expression. RvD1 also increased the Nrf2 and its downstream targets NQO1 and HO-1 mRNA expression. Regarding cytokines, RvD1 inhibited UVB-induced production of IL-1ß, IL-6, IL-33, TNF-α, TGF-ß, and IL-10. These immuno-biochemical alterations by RvD1 treatment had as consequence the reduction of UVB-induced epidermal thickness, sunburn and mast cell counts, and collagen degradation. Therefore, RvD1 inhibited UVB-induced skin oxidative stress and inflammation, rendering this resolving lipid mediator as a promising therapeutic agent.
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The idiopathic inflammatory bowel diseases (IBD) comprise two types of chronic intestinal disorders: Crohn's disease and ulcerative colitis. Recruited neutrophils and macrophages contribute to intestinal tissue damage via production of ROS and NF-κB-dependent pro-inflammatory cytokines. The introduction of anti-TNF-α therapies in the treatment of IBD patients was a seminal advance. This therapy is often limited by a loss of efficacy due to the development of adaptive immune response, underscoring the need for novel therapies targeting similar pathways. Vinpocetine is a nootropic drug and in addition to its antioxidant effect, it is known to have anti-inflammatory and analgesic properties, partly by inhibition of NF-κB and downstream cytokines. Therefore, the present study evaluated the effect of the vinpocetine in a model of acid acetic-induced colitis in mice. Treatment with vinpocetine reduced edema, MPO activity, microscopic score and macroscopic damage, and visceral mechanical hyperalgesia. Vinpocetine prevented the reduction of colonic levels of GSH, ABTS radical scavenging ability, and normalized levels of anti-inflammatory cytokine IL-10. Moreover, vinpocetine reduced NF-κB activation and thereby NF-κB-dependent pro-inflammatory cytokines IL-1ß, TNF-α, and IL-33 in the colon. Thus, we demonstrate for the first time that vinpocetine has anti-inflammatory, antioxidant, and analgesic effects in a model of acid acetic-induced colitis in mice and deserves further screening to address its suitability as an approach for the treatment of IBD.
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Colite/tratamento farmacológico , NF-kappa B/efeitos dos fármacos , Alcaloides de Vinca/farmacologia , Ácido Acético , Analgésicos , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Colite/induzido quimicamente , Camundongos , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologiaRESUMO
The present study aimed to evaluate the effects of the flavonoid quercetin (3,3´,4´,5,7-pentahydroxyflavone) in a mice model of intense acute swimming-induced muscle pain, which resembles delayed onset muscle soreness. Quercetin intraperitoneal (i.p.) treatment dose-dependently reduced muscle mechanical hyperalgesia. Quercetin inhibited myeloperoxidase (MPO) and N-acetyl-ß-D- glucosaminidase (NAG) activities, cytokine production, oxidative stress, cyclooxygenase-2 (COX-2) and gp91phox mRNA expression and muscle injury (creatinine kinase [CK] blood levels and myoblast determination protein [MyoD] mRNA expression) as well as inhibited NFκB activation and induced Nrf2 and HO-1 mRNA expression in the soleus muscle. Beyond inhibiting those peripheral effects, quercetin also inhibited spinal cord cytokine production, oxidative stress and glial cells activation (glial fibrillary acidic protein [GFAP] and ionized calcium-binding adapter molecule 1 [Iba-1] mRNA expression). Concluding, the present data demonstrate that quercetin is a potential molecule for the treatment of muscle pain conditions related to unaccustomed exercise.
Assuntos
Dor Aguda/fisiopatologia , Nociceptividade/efeitos dos fármacos , Sistema Nervoso Periférico/fisiopatologia , Quercetina/farmacologia , Medula Espinal/efeitos dos fármacos , Natação , Dor Aguda/etiologia , Animais , Camundongos , Medula Espinal/fisiopatologiaRESUMO
Neurocysticercosis is the most common helminthic infection of the CNS but its diagnosis remains difficult. Clinical manifestations are nonspecific, most neuroimaging findings are not pathognomonic, and some serologic tests have low sensitivity and specificity. The authors provide diagnostic criteria for neurocysticercosis based on objective clinical, imaging, immunologic, and epidemiologic data. These include four categories of criteria stratified on the basis of their diagnostic strength, including the following: 1) absolute--histologic demonstration of the parasite from biopsy of a brain or spinal cord lesion, cystic lesions showing the scolex on CT or MRI, and direct visualization of subretinal parasites by funduscopic examination; 2) major--lesions highly suggestive of neurocysticercosis on neuroimaging studies, positive serum enzyme-linked immunoelectrotransfer blot for the detection of anticysticercal antibodies, resolution of intracranial cystic lesions after therapy with albendazole or praziquantel, and spontaneous resolution of small single enhancing lesions; 3) minor--lesions compatible with neurocysticercosis on neuroimaging studies, clinical manifestations suggestive of neurocysticercosis, positive CSF enzyme-linked immunosorbent assay for detection of anticysticercal antibodies or cysticercal antigens, and cysticercosis outside the CNS; and 4) epidemiologic--evidence of a household contact with Taenia solium infection, individuals coming from or living in an area where cysticercosis is endemic, and history of frequent travel to disease-endemic areas. Interpretation of these criteria permits two degrees of diagnostic certainty: 1) definitive diagnosis, in patients who have one absolute criterion or in those who have two major plus one minor and one epidemiologic criterion; and 2) probable diagnosis, in patients who have one major plus two minor criteria, in those who have one major plus one minor and one epidemiologic criterion, and in those who have three minor plus one epidemiologic criterion.
Assuntos
Neurocisticercose/diagnóstico , HumanosRESUMO
A microplate-type enzyme-linked immunosorbent assay for the detection of Taenia species antigen in human feces was tested in field studies undertaken in two Guatemalan communities. The test was based on immunoglobulin G antibodies from a rabbit hyperimmunized to Taenia solium proglottides. Comparison was made with microscopy and patient interviews as a means of diagnosis. The coproantigen test result was positive in 79 of the 1,582 fecal samples examined. Parasitologic confirmation was made in 55 of these cases. The coproantigen test was the most sensitive technique used, detecting 2.6 times as many confirmed cases of taeniasis as microscopy, which diagnosed 21 cases. Only one case was detected by interviewing. Microscopy revealed on false-negative coproantigen result. Mass treatment of the population did not result in the detection of any additional cases. Twelve coproantigen-positive results were categorized as unconfirmed and an additional 12 as putative false-positive results, giving an overall specificity of 99.2% for the coproantigen test. Of the 34 taeniid tapeworms identified to the species level, all were T. solium. The practicalities of the use of such a test in epidemiologic studies on human taeniasis are discussed.