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Chem Biol Interact ; 329: 109220, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32763245


The sepsis is considered as serious clinic-pathological condition related with high rate of morbidity and mortality in critical care settings. In the proposed study, the hydrazides derivatives N-(benzylidene)-2-((2-hydroxynaphthalen-1-yl)diazenyl)benzohydrazides (1-2) (NCHDH and NTHDH) were investigated against the LPS-induced sepsis in rodents. The NCHDH and NTHDH markedly improved the physiological sign and symptoms associated with the sepsis such as mortality, temperature, and clinical scoring compared to negative control group, which received only LPS (i.p.). The NCHDH and NTHDH also inhibited the production of the NO and MPO compared to the negative control. Furthermore, the treatment control improved the histological changes markedly of all the vital organs. Additionally, the Masson's trichrome and PAS (Periodic Acid Schiff) staining also showed improvement in the NCHDH and NTHDH treated group in contrast to LPS-induced group. The antioxidants were enhanced by the intervention of the NCHDH and NTHDH and the level of the MDA and POD were attenuated marginally compared to the LPS-induced group. The hematology study showed marked improvement and the reversal of the LPS-induced changes in blood composition compared to the negative control. The synthetic function of the liver and kidney were preserved in the NCHDH and NTHDH treated group compared to the LPS-induced group. The NCHDH and NTHDH markedly enhanced the Nrf2, HO-1 (Heme oxygenase-1), while attenuated the Keap1 and TRPV1 expression level as compared to LPS treated group. Furthermore, the NCHDH and NTHDH treatment showed marked increased in the mRNA expression level of the HSP70/90 proteins compared to the negative control.

Hidrazinas/farmacologia , Insuficiência de Múltiplos Órgãos/etiologia , Sepse/etiologia , Transdução de Sinais/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Heme Oxigenase-1/metabolismo , Hidrazinas/química , Hidrazinas/uso terapêutico , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Lipopolissacarídeos/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/mortalidade , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Sepse/tratamento farmacológico , Sepse/mortalidade , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo
Int Immunopharmacol ; 80: 106209, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32004924


The present study investigated the effect of the continentalic acid (CNT) isolated from the Aralia Continentalis against the LPS and E. coli-induced nephrotoxicity. The LPS and E. coli administration markedly altered the behavioral parameters including spontaneous pain, tail suspension and survival rate. However, the treatment with CNT dose dependently improved the behavioral parameters. The CNT treatment significantly improved the renal functions test (RFTs) and hematological parameters following LPS and E. coli-induced kidney injury. Furthermore, the LPS and E. coli administration markedly compromised the anti-oxidant enzymes and enhanced the oxidative stress markers. However, the CNT treatment markedly enhanced the anti-oxidants enzymes such as GSH, GST, Catalase and SOD, while attenuated the oxidative stress markers such as MDA and POD. The MPO enzyme is widely used marker for the neutrophilic infiltration, the LPS and E. coli administration markedly increased the MPO activity. However, the CNT treatment markedly attenuated the MPO activity in both LPS and E. coli-induced kidney injury. Furthermore, the CNT treatment markedly attenuated the NO production compared to the LPS and E. coli-induced kidney injury group. Additionally, the CNT treatment improved the histological parameters markedly (H and E, PAS and Masson's trichome staining) and protect the kidney from the inflammatory insult of the LPS and E. coli evidently. The comet assay revealed marked DNA damage, however, the CNT treatment markedly prevented the LPS and E. coli-induced kidney damage. The CNT treatment markedly enhanced the expression of Nrf2, while attenuated the iNOS expression in both models of kidney injury.

Lesão Renal Aguda/tratamento farmacológico , Diterpenos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Lesão Renal Aguda/imunologia , Lesão Renal Aguda/patologia , Animais , Aralia/química , Modelos Animais de Doenças , Diterpenos/uso terapêutico , Escherichia coli/imunologia , Humanos , Rim/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Lipopolissacarídeos/imunologia , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/imunologia , Substâncias Protetoras/uso terapêutico
Life Sci ; 239: 116888, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31639401


5-Fluorouracil (5-FU)-induced intestinal mucositis (IM) is one of the most common oncological problem. It involves serious clinical consequences such as diarrhea, erythematous lesions of mucosa, and eventually development of ulcers accompanied by severe pain. The aim of the present study was to demonstrate the mucoprotective effects of Saikosaponin-A in 5-FU-induced intestinal mucositis in mice. Mucositis was induced in BALB/c mice by intraperitoneal injection of 5-FU (50 mg/kg/day) for three consecutive days and IM was assessed by both behavioral and histochemical analysis. While, Saikosaponin-A (1, 5, 10 mg/kg/day) was administered 1 h before 5-FU injection for consecutive seven days. Pre-treatment of Saikosaponin-A significantly ameliorated the severity of mucositis reflected as food intake, body weight loss, severity of diarrhea and mortality rate in a dose depended manner as compared to mice treated with 5-FU. Moreover, histopathological analysis furthered reinforced the mucoprotective potential of Saikosaponin-A against 5-FU-induced intestinal abnormalities referred as villus atrophy, mitotic crypt stem cells damage, inflammatory cells infiltration, vacuolization and edema. Furthermore, Saikosaponin-A administration strongly inhibited pro-inflammatory mediators (TNF-α, COX-2, IL-1ß and IL-6) and apoptotic markers (p-JNK, Casp-3). Saikosaponin-A pre-treatment significantly reduced the production of nitric oxide (NO) in intestinal tissue, inhibited acetic acid-induced Evans blue vascular permeability. The Siaikosaponin-A treatment markedly enhanced the anti-oxidants enzymes (Nrf2, HO-1, SOD, GSH, GST and Catalase), while decreased the oxidative stress markers i.e. Malonaldehde (MDA). Hence, these data suggest that Saikosaponin-A maybe a potential candidate for the treatment of chemotherapy-induced intestinal mucositis.

Mucosa Intestinal/efeitos dos fármacos , Mucosite/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Animais , Antimetabólitos Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Citocinas , Diarreia/induzido quimicamente , Modelos Animais de Doenças , Fluoruracila/farmacologia , Mucosa Intestinal/patologia , Intestinos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mucosite/metabolismo , Ácido Oleanólico/metabolismo , Ácido Oleanólico/farmacologia , Saponinas/metabolismo
BMC Pharmacol Toxicol ; 20(1): 57, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511086


BACKGROUND: Poncirin is flavanone derivative (isolated from Poncirus trifoliata) with known pharmacological activities such as anti-tumor, anti-osteoporotic, anti-inflammatory and anti-colitic. The present study aimed to explore the anti-allodynic and anti-hyperalgesic potentials of poncirin in murine models of inflammatory pain. METHODS: The analgesic potential of poncirin was evaluated in formalin-, acetic acid-, carrageenan- and Complete Freund's Adjuvant (CFA)-induced inflammatory pain models in mice. Anti-allodynic and anti-hyperalgesic activities were measured using Von Frey filaments, Randall Selitto, hotplate and cold acetone tests. The serum nitrite levels were determined using Griess reagent. The Quantitative Real-time PCR (qRT-PCR) was performed to assess the effect of poncirin on mRNA expression levels of inflammatory cytokines and anti-oxidant enzymes. RESULTS: Intraperitoneal administration of poncirin (30 mg/kg) markedly reduced the pain behavior in both acetic acid-induced visceral pain and formalin-induced tonic pain models used as preliminary screening tools. The poncirin (30 mg/kg) treatment considerably inhibited the mechanical hyperalgesia and allodynia as well as thermal hyperalgesia and cold allodynia. The qRT-PCR analysis showed noticeable inhibition of pro-inflammatory cytokines (mRNA expression levels of TNF-α, IL-1ß and IL-6) (p < 0.05) in poncirin treated group. Similarly, poncirin treatment also enhanced the mRNA expressions levels of anti-oxidant enzymes such as transcription factor such as nuclear factor (erythroid-derived 2)-like 2 (Nrf2) (p < 0.05), heme oxygenase (HO-1) (p < 0.05) and superoxide dismutase (SOD2) (p < 0.05). Chronic treatment of poncirin for 6 days did not confer any significant hepatic and renal toxicity. Furthermore, poncirin treatment did not altered the motor coordination and muscle strength in CFA-induced chronic inflammatory pain model. CONCLUSION: The present study demonstrated that poncirin treatment significantly reduced pain behaviors in all experimental models of inflammatory pain, suggesting the promising analgesic potential of poncirin in inflammatory pain conditions.

Anti-Inflamatórios não Esteroides/uso terapêutico , Dor Crônica/tratamento farmacológico , Flavonoides/uso terapêutico , Hiperalgesia/tratamento farmacológico , Ácido Acético/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/toxicidade , Carragenina/antagonistas & inibidores , Dor Crônica/induzido quimicamente , Modelos Animais de Doenças , Flavonoides/toxicidade , Formaldeído/efeitos adversos , Hiperalgesia/induzido quimicamente , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Hipersensibilidade Respiratória/tratamento farmacológico
Int Immunopharmacol ; 61: 306-316, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29909234


In the current study, the puerarin was investigated for both acute Carrageenan and chronic CFA-induced inflammatory pain models. The Puerarin treatment significantly attenuated (P < 0.001) the mechanical hyperalgesia and mechanical allodynia in both Carrageenan and CFA-induced hyperalgesia. The Puerarin treatment also remarkably reduced (p < 0.001) the thermal hyperalgesic responses in both acute Carrageenan as well as chronic CFA-induced models. Furthermore, the Puerarin administration was also associated with significant inhibition of (p < 0.001) paw edema in both Carrageenan and CFA-induced models. The inflammatory mediators such as IL-1ß, IL-6, TNF-α and vascular endothelial growth factor (VEGF) are significantly enhanced during inflammatory conditions, however, the Puerarin administration significantly altered (P < 0.001) the mRNA expression levels of these mediators. Additionally, the Puerarin treatment also significantly enhanced (P < 0.001) the mRNA expressions levels of the anti-oxidant enzymes such as Nrf2, HO-1 and SOD2. The Puerarin treatment is associated with significant (P < 0.001) inhibition of the acetic acid-induced Evans blue vascular permeability. Moreover, the concentration of Puerarin in various tissues was analyzed using High-performance liquid chromatography (HPLC) and the results showed that the Puerarin was significantly distributed towards the peripheral tissues such as liver and kidney and less distributed towards the brain.

Anti-Inflamatórios/uso terapêutico , Edema/tratamento farmacológico , Inflamação/tratamento farmacológico , Isoflavonas/uso terapêutico , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Dor/tratamento farmacológico , Animais , Permeabilidade Capilar/efeitos dos fármacos , Carragenina , Citocinas/metabolismo , Modelos Animais de Doenças , Edema/induzido quimicamente , Humanos , Inflamação/induzido quimicamente , Mediadores da Inflamação/metabolismo , Rim/patologia , Fígado/patologia , Masculino , Camundongos , Dor/induzido quimicamente , Pueraria/imunologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
Inflammopharmacology ; 26(4): 1037-1049, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29470693


Chronic inflammation is pathologically associated with various clinical conditions such as rheumatoid arthritis. Several anti-inflammatory and analgesic drugs currently available in market presents a wide range of problems. Therefore, the current study was aimed to evaluate anti-inflammatory and analgesic activities of newly synthesized compound 2-(5-mercapto-1,3,4-oxadiazol-2-yl)-N-propylbenzenesulphonamide (MOPBS). Carrageenan and CFA-induced models were developed for evaluation of anti-inflammatory and analgesic activity. Quantitative real-time PCR (qRT-PCR) was performed to determine the mRNA expression levels of inflammatory mediators. Pain behaviours were evaluated by performing Von Frey, Randall Selitto, cold acetone and hot plate test respectively. X-ray imaging and haematoxylin and eosin (H&E) staining were performed for examination of soft tissues of treated mice paw. Additionally, Kodzeila's screen test and weight test were performed for determination of any side effects on motor function and muscle strength. Acute pretreatment of animals with MOPBS (1, 10, 50 and 100 mg/kg, i.p.) produced a significant reduction of paw oedema against carrageenan-induced acute inflammation as well as notable inhibition of mechanical hyperalgesia, allodynia and thermal hyperalgesia. Similarly, in chronic inflammation model, administration of MOPBS (50 mg/kg, i.p.) produced a remarkable reduction of paw oedema. Additionally, MOPBS pretreatment showed a significant inhibition of thermal hyperalgesia, mechanical allodynia, and mechanical hyperalgesia in chronic arthritis model. Several pro-inflammatory mediators such as nitric oxide (NO), vascular endothelial growth factor (VEGF), interleukins (IL-1ß, IL-6) and tumor necrosis factor-α (TNF-α) were inhibited by MOPBS treatment in blood plasma and paw tissues, respectively. MOPBS also enhanced the mRNA expression levels of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), superoxide dismutase (SOD2) and heme oxygenase (HO-1) and in turn reduced arthritis severity and inflammation. Furthermore, anti-inflammatory data were confirmed by X-rays and histological analysis. MOPBS pretreatment did not produce any apparent toxic effect on gastric, kidney and liver function and on muscle strength and motor function. Hence, the present data suggest that MOPBS might be a candidate for several chronic inflammatory diseases such RA and other auto-immune diseases.

Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Antirreumáticos/farmacologia , Oxidiazóis/farmacologia , Sulfonamidas/farmacologia , Analgésicos/administração & dosagem , Analgésicos/toxicidade , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/toxicidade , Antirreumáticos/administração & dosagem , Antirreumáticos/toxicidade , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Carragenina , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Edema/tratamento farmacológico , Edema/patologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/patologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Masculino , Camundongos , Oxidiazóis/administração & dosagem , Oxidiazóis/toxicidade , Dor/tratamento farmacológico , Dor/patologia , Reação em Cadeia da Polimerase em Tempo Real , Sulfonamidas/administração & dosagem , Sulfonamidas/toxicidade