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BACKGROUND: Obstructive nephropathy is a condition often caused by urinary tract obstruction either anatomical (e.g., tumors), mechanical (e.g., urolithiasis), or compression (e.g., pregnancy) and can progress to chronic kidney disease (CKD). Studies have shown sexual dimorphism in CKD, where males were found to have a more rapid decline in kidney function following kidney injury compared to age-matched females. Protocatechuic acid (PCA), an anti-oxidant and anti-inflammatory polyphenolic compound, has demonstrated promising effects in mitigating drug-induced kidney injuries. The current study aims to explore sexual dimorphism in kidney injury after unilateral ureteral obstruction (UUO) and assess whether PCA treatment can mitigate kidney injury in both sexes. METHODS: UUO was induced in 10-12 weeks old male and female C57BL/6J mice. Mice were categorized into four groups (n = 6-8/group); Sham, Sham plus PCA (100 mg/kg, I.P daily), UUO, and UUO plus PCA. RESULTS: After 2 weeks of induction of UUO, markers of kidney oxidative stress (TBARs), inflammation (IL-1α and IL-6), tubular injury (neutrophil gelatinase-associated lipocalin, NGAL and urinary kidney injury molecule-1, KIM-1), fibrosis (Masson's trichrome staining, collagen IV expression, MMP-2 and MMP-9) and apoptosis (TUNEL+ cells, active caspase-1 and caspase-3) were significantly elevated in both males and females relative to their sham counterparts. Males exhibited significantly greater kidney oxidative stress, inflammation, fibrosis, and apoptosis after induction of UUO when compared to females. PCA treatment significantly attenuated UUO-induced kidney injury, inflammation, fibrosis, and apoptosis in both sexes. CONCLUSION: Our findings suggest a differential gender response to UUO-induced kidney injury with males being more sensitive to UUO-induced kidney inflammation, fibrosis, and apoptosis than age-matched females. Importantly, PCA treatment reduced UUO-induced kidney injury in a sex-independent manner which might be attributed to its anti-oxidant, anti-inflammatory, anti-fibrotic, and anti-apoptotic properties.
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Hidroxibenzoatos , Nefropatias , Insuficiência Renal Crônica , Obstrução Ureteral , Feminino , Camundongos , Masculino , Animais , Obstrução Ureteral/complicações , Obstrução Ureteral/tratamento farmacológico , Caracteres Sexuais , Antioxidantes/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Rim , Nefropatias/tratamento farmacológico , Nefropatias/etiologia , Nefropatias/prevenção & controle , Insuficiência Renal Crônica/metabolismo , Apoptose , Inflamação/metabolismo , Fibrose , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêuticoRESUMO
This study aimed to evaluate the possible ameliorative effects of saroglitazar (SAR) on aspects of hepatic injury in dexamethasone (DEX)-induced nonalcoholic steatohepatitis (NASH) in rats. Wistar rats received SAR (2 or 4 mg/kg/day, orally) or metformin (MET, 500 mg/kg/day, orally) for one week before and concurrently with DEX administration (8 mg/kg/day, i.p., for 6 days. Control and drug control groups received vehicle or the higher dose of SAR, respectively. At the end of the experiment, an oral glucose tolerance test (OGTT) was conducted, serum hepatic function parameters and lipid profile were assessed, and hepatic histological changes were evaluated. Moreover, hepatic p-Akt/Akt ratios, malondialdehyde (MDA) content, SREBP-1, FOXO1, LC3, cleaved caspase-3, and p-MLKL protein levels were determined. Furthermore, hepatic immunohistochemical expressions of FOXO1, caspase-3, Bcl-2, LC3, and P62 were examined. SAR (mainly at 4 mg/kg/day) significantly improved Area under the OGTT curve (P < 0.0001), hepatic function parameters, lipid profile, and hepatic histopathological features in DEX-administered rats. Moreover, SAR significantly attenuated DEX-induced increases in hepatic MDA content (P < 0.05), SREBP-1 levels (P < 0.0001), and nuclear FOXO1, caspase-3, LC3, P62, and p-MLKL protein expressions (P < 0.0001). Furthermore, SAR significantly enhanced hepatic p-Akt/Akt ratio and Bcl-2 protein expression in DEX-administered rats (P < 0.0001). The higher dose of SAR showed greater hepatoprotective effects compared to its corresponding lower dose and MET in most assessments, approaching levels similar to the control group. SAR mitigated hepatic injury associated with DEX-induced NASH in rats, suggesting it might be a potential hepatoprotective drug for patients with or at high risk of NASH.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Fenilpropionatos , Pirróis , Humanos , Ratos , Animais , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Caspase 3 , Proteína de Ligação a Elemento Regulador de Esterol 1 , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Necroptose , Apoptose , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Dexametasona/farmacologia , Lipídeos , AutofagiaRESUMO
Roflumilast (ROF), a highly selective phosphodiesterase-4 inhibitor, has proven anti-inflammatory and immunomodulatory effects on the pulmonary system. However, the protective effects of ROF on cadmium (Cd)-induced hepatic and testicular injury has never been investigated. Adult male Sprague Dawley rats were acutely intoxicated with CdCl2 (3 mg/Kg, ip, qd, for 5 days). In treatment groups, ROF was administered in two doses (1.5 & 3 mg/Kg, po, qd, for 5 days) 2 h prior to CdCl2 intoxication. The results demonstrated that the therapeutic potential of ROF can extend beyond the pulmonary system. The histopathological manifestation of Cd in the liver and testes were evidently mitigated by ROF prophylaxis. This study unraveled the multi-faceted ROF protective mechanisms, these comprise (i) reviving normal liver and testicular architecture, (ii) lessen immune cell infiltration in injured tissues (iii) restoration of cellular oxidant status (GSH, SOD, NO and MDA), (iv) shielding pro-inflammatory signaling pathways (NF-κB, NLRP3, IL-1ß axis), (v) dampening endoplasmic reticulum stress (IRE-1), (vi) mitigating apoptotic injury (caspase-3), (vii) restoring the integrity of blood testes barrier (Cathepsin-D) and (viii) promoting the regenerative potentials of injured testes (SDF-1). In conclusion, ROF is a promising anti-inflammatory and anti-oxidative candidate in Cd-induced hepatic and testicular injury.
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Antioxidantes , Cádmio , Ratos , Masculino , Animais , Cádmio/toxicidade , Cádmio/metabolismo , Antioxidantes/farmacologia , Ratos Wistar , Ratos Sprague-Dawley , Estresse Oxidativo , Inflamação/metabolismo , Fígado/patologia , Anti-Inflamatórios/farmacologiaRESUMO
BACKGROUND: Paraquat (PQ, 1,1'-dimethyl-4-4'-bipyridinium dichloride) is a highly toxic quaternary ammonium herbicide widely used in agriculture. It exerts its toxic effects mainly as a result of its redox cycle via the production of superoxide anions in organisms, leading to an imbalance in the redox state of the cell causing oxidative damage and finally cell death. The aim of this study was to estimate the beneficial protective role of nilotinib (NIL) on PQ-induced hepatic and pulmonary toxicity in rats. METHODS: Male wistar rats were randomly divided into four groups, namely control, PQ (15 mg/kg), PQ plus NIL (5 mg/kg) and PQ plus NIL (10 mg/kg). NIL (5 and 10 mg/kg/day) was taken by oral syringe for five days followed by a single intra-peritoneal administration of PQ (15 mg/kg) on sixth day. RESULTS: Pretreatment with NIL relieved the histological damage in liver and lung tissues and improved hepatic biochemical markers. It significantly (p < 0.05) reduced serum levels of ALT, AST, ALP, Y-GT and total bilirubin while increased that of albumin. Meanwhile, NIL significantly (p < 0.05) reduced oxidative stress markers via reduction of malondialdhyde (MDA) and elevation of glutathione (GSH) contents in liver and lung tissues. In addition, it significantly (p < 0.05) decreased the inflammation by reducing hepatic and pulmonary tumor necrosis factor alpha (TNF-α) and nuclear transcription factor kappa B (NF-KB/p65) contents. Nilotinib also down-regulated apoptosis by reducing cysteinyl aspartate-specific proteinase-3 (caspase-3). Furthermore, it upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and microtubule-associated protein 1A/1B-light chain 3 II (LC3II) in liver and lung tissues. SIGNIFICANCE: NIL suppressed PQ-induced inflammation, oxidative stress and apoptosis in liver and lung tissues by modulating Nrf2/Nf-kB axis.
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Concanavalin A (ConA) is an established model for inducing autoimmune hepatitis (AIH) in mice, mimicking clinical features in human. The aimof the current study is to explore the possible protective effect of celecoxib, a cyclooxygenase-2 inhibitor,on immunological responses elicited in the ConA model of acute hepatitis. ConA (20 mg/kg) was administered intravenously to adult male mice for 6 h. Prior to ConA intoxication, mice in the treatedgroups received daily doses of celecoxib (30 and 60 mg/kg in CMC) for 7 days. Results revealed that administration of celecoxib 60 mg/kg for 7 days significantly protected the liver from ConA-induced liver damage revealed by significant decrease in ALT and AST serum levels. Celecoxib 30 and 60 mg/kg pretreatment enhanced oxidant/antioxidant hemostasis by significantreduction of MDA and NO content and increase hepatic GSH contents and SOD activity. In addition, celecoxib 30 and 60 mg/kg caused significant increase in hepatic nuclear factor erythroid 2-related factor 2 (Nrf2) and the stress protein heme oxygenase-1 (HO-1) levels. Moreover, celecoxib 30 and 60 mg/kg inhibited the release of proinflammatory markers including IL-1ß and TNF-α along with significant decrease in p-JNK, AKT phosphorylation ratio and caspase-3 expression. Besides, Con A was correlated to high expression of cyclooxygenase COX-2 and this increasing was improved by administration of celecoxib. These changes were in good agreement with improvement in histological deterioration. The protective effect of celecoxib was also associated with significant reduction of autophagy biomarkers (Beclin-1 and LC3II). In conclusion, celecoxib showed antioxidant, anti-inflammatory, anti-apoptotic and anti-autophagy activity against Con A-induced immune-mediated hepatitis. These effects could be produced by modulation of Nrf2/HO-1, IL-1B /p-JNK/p-AKT, JNK/caspase-3, and Beclin-1/LC3II signaling pathways.
Assuntos
Hepatite Autoimune , Sistema de Sinalização das MAP Quinases , Camundongos , Masculino , Humanos , Animais , Celecoxib/farmacologia , Antioxidantes/farmacologia , Concanavalina A/metabolismo , Ciclo-Oxigenase 2/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Caspase 3/metabolismo , Heme Oxigenase-1/metabolismo , Proteína Beclina-1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fígado/patologia , Hepatite Autoimune/patologiaRESUMO
RATIONALE: Ulcerative colitis (UC) is a chronic immune-mediated disease characterized by recurrent inflammation, damage, and alteration of the large intestine's mucosal and submucosal surfaces. The purpose of this research was to evaluate the impact of tyrosine kinase inhibitor (imatinib) on experimentally induced UC in rats via acetic acid (AA). METHODS: Male rats were randomly assigned to four groups: control, AA, AA + imatinib (10 mg/kg), and AA + imatinib (20 mg/kg). Imatinib (10 and 20 mg/kg/day) was orally supplied by oral syringe for one week before induction of UC. On the eighth day, Rats received enemas containing a 4 % solution of acetic acid to induce colitis. One day after inducing colitis, rats were euthanized and their colons were subjected to morphological, biochemical, histological, and immunohistochemical analysis. RESULTS: Imatinib pretreatment significantly decreased macroscopic and histological damage scores, decreased disease activity index as well as colon mass index. In addition, imatinib successfully lowered the levels of malondialdehyde (MDA) in colonic tissues and enhanced superoxide dismutase activity (SOD) and glutathione content (GSH). Imatinib also reduced colonic levels of inflammatory interleukins (IL-23, IL-17, IL-6), JAK2 and STAT3. Furthermore, imatinib suppressed nuclear transcription factor kappa B (NF-kB/p65) level, and COX2 expression in colonic tissues. SIGNIFICANCE: Imatinib may be a viable therapy option for UC as it halts the interaction network of NF-kB/JAK2/STAT3/COX2 signaling pathway.
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Colite Ulcerativa , Colite , Ratos , Masculino , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , NF-kappa B/metabolismo , Mesilato de Imatinib/farmacologia , Ciclo-Oxigenase 2/metabolismo , Colo/metabolismo , Transdução de Sinais , Colite/patologia , Glutationa/metabolismo , Ácido Acético , Janus Quinase 2/metabolismoRESUMO
Type-2 diabetes (T2DM) is known to be highly associated with increased risk for vascular complications including peripheral arterial diseases (PAD). Critical limb ischemia (CLI) is the most advanced stage of PAD. Current therapeutic options for diabetic patients experiencing vascular complications are limited to surgical revascularization with no effective pharmacotherapy available for clinical settings. This study is dedicated to evaluate the angiogenic potential of candesartan an angiotensin-II receptor blocker in an experimental model of vascular complications associating T2DM. T2DM was induced in rats through feeding with high fat diet for 6â¯weeks, followed by injection with streptozotocin (STZ, 30â¯mg/kg; i.p). After establishment of T2DM, unilateral CLI was induced through the ligation and excision of superficial femoral artery. Candesartan treatment (10 or 30â¯mg/kg; orally) was initiated one day post CLI and thereafter once daily for up to 14â¯days. T2DM rats that underwent CLI demonstrated impaired angiogenic signaling, increased inflammation and apoptosis in gastrocnemius muscle (GC). Candesartan reversed ischemic insult in T2DM rats subjected to unilateral CLI and induced reparative angiogenesis that was evident by increase in p-PI3K/PI3K, p-Akt/Akt, p-eNOS/eNOS, p-VEGFR2/VEGFR2 ratios, and VEGF levels. Candesartan treatment also increased levels of HO-1; while decreased caspase-3 apoptotic marker and levels of inflammatory markers; NF-κB and TNF-α, all of which were accompanied by preserved histological manifestations of GC muscles. Candesartan was able to combat limb ischemia under diabetic conditions which could pave the way for its therapeutic utility for diabetic patients experiencing vascular complications in clinical setting.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Ratos , Animais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Diabetes Mellitus Experimental/metabolismo , Isquemia/tratamento farmacológico , Isquemia/metabolismo , Transdução de Sinais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Neovascularização FisiológicaRESUMO
BACKGROUND: Lipopolysaccharide (LPS), an endotoxin within gram-negative bacteria, is associated with systemic acute inflammatory response after invading living tissues and results in sepsis. The liver and kidney are both major target organs in sepsis. Septic acute hepatic-renal injury is a serious clinical condition with high risk of morbidity and mortality. Nevertheless, effective treatment is still lacking. AIM: This study highlights saroglitazar (SAR), a dual PPAR-α/γ agonist, as a proposed prophylactic drug against LPS-induced hepatic-renal injury. MAIN METHODS: Rats were pretreated with SAR (2 and 4 mg/kg/day) for 15 days, while sepsis was induced by LPS injection (10 mg/kg) on day 15 one hour following SAR oral administration. KEY FINDINGS: SAR pretreatment could successfully mitigate LPS-induced hepatic-renal injury, evidenced by enhancement of renal and hepatic functions and a decrease of tissue pathological injury. Meanwhile, SAR alleviated LPS-induced oxidative stress; it reduced malondialdehyde (MDA) levels and ameliorated decreased levels of superoxide dismutase (SOD) and glutathione (GSH). LPS-induced elevations in hepatic and renal nuclear factor-kappa B (NF-κB), phosphorylated inhibitor of kappa B alpha (p-IκBα), interferon-beta (IFN-ß), and hepatic high mobility group box-1 (HMGB-1) contents were significantly attenuated in SAR-treated groups. SAR showed an advantageous impact against LPS-induced activation of non-canonical inflammasome and pyroptosis via a significant reduction in cysteinyl aspartate-specific proteinase-11 (Caspase-11) and gasdermin D (GSDMD) expressions. Moreover, Nucleotide-Binding Oligomerization Domain (NOD)-Like Receptor Protein 3 (NLRP3) inflammasome activation with concomitant expression and activation of caspase-1 and release of interleukin-1beta (IL-1ß) were considerably diminished following SAR pretreatment. SIGNIFICANCE: SAR could be considered a prophylactic anti-inflammatory antioxidant drug against LPS-induced liver and kidney injury.
Assuntos
Injúria Renal Aguda , Inflamassomos , Ratos , Animais , Inflamassomos/metabolismo , Lipopolissacarídeos/farmacologia , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Fígado/metabolismo , Rim , NF-kappa B/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Glutationa/metabolismo , Anti-Inflamatórios/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismoRESUMO
The current study inspects the impact of nilotinib (Nil) on liver damage caused by acetaminophen (APAP). Adult male mice were pre-treated with nilotinib (Nil,5 and 10 mg/kg) orally once daily for 7 days followed by a single intraperitoneal administration of acetaminophen (APAP, 200 mg/kg) on the 7th day. The results indicated that nilotinib significantly decreased APAP-induced elevation of biochemical markers (ALT, AST, ALP, LDH, ɤ GT, and total bilirubin). Additionally, nilotinib significantly increased hepatic GSH and SOD content, while decreased MDA content. Nil significantly suppressed the expression of HIF-1α and VEGF. Histopathological examination of hepatic tissue from Nil-treated mice revealed that Nil reduced acetaminophen-induced necrosis.
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Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Camundongos , Masculino , Animais , Fator A de Crescimento do Endotélio Vascular , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fígado/patologia , Transdução de Sinais , Superóxido Dismutase , Bilirrubina , Estresse OxidativoRESUMO
AIMS: Chronic kidney disease (CKD) is a global non-communicable health problem. Fibrosis is considered the base and the fate of CKD; thus, the goal of this study was to evaluate the effects of sodium molybdate on cisplatin-induced CKD model and demonstrate the possible involved mechanisms. MATERIALS AND METHODS: In cisplatin model, Wistar rats were challenged with cisplatin (1 mg/kg, i.p.) twice weekly for ten weeks. Sodium molybdate (100 and 200 mg/kg, orally) was given one-week prior cisplatin and was continued daily for the next ten weeks. KEY FINDINGS: Administration of sodium molybdate amended kidney function and significantly reduced the pathological changes in renal histopathological sections. Moreover, it modulates oxidative stress parameters by increasing the levels of SOD and GSH and decreasing the level of MDA. Likewise, in renal homogenate, sodium molybdate attenuated inflammation that was revealed by NF-κB and TNF-α levels significant reduction. Additionally, it ameliorated fibrosis that was indicated by decreased Masson's trichome staining in cortex and medulla. Immunohistochemical staining of renal sections against TGF-ß1 showed reduction of positive glomerular and tubular protein expression. Additionally, it decreased profibrotic Smad3 level and increased antifibrotic Smad7 level. SIGNIFICANCE: Administration of sodium molybdate demonstrated a hopeful suppressor effect on cisplatin-induced CKD/fibrosis in rat model. This effect may be through the inhibition pof TGF-ß/Smad signaling pathway and up-regulation of Smad7 expression leading to decreased extracellular collagen accumulation. Moreover, they could ameliorate the inflammation through NF-κB and TNF-α levels reduction, decrease in ROS, and retrieval of antioxidant defenses.
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Insuficiência Renal Crônica , Proteínas Smad , Animais , Cisplatino/metabolismo , Cisplatino/toxicidade , Fibrose , Inflamação , Molibdênio , NF-kappa B/metabolismo , Ratos , Ratos Wistar , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/patologia , Transdução de Sinais , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
INTRODUCTION: Asthma is a chronic lung disease that injures and constricts the airways. This study evaluates the effects of agmatine on ovalbumin (OVA)-induced allergic inflammation of the airways. METHODS: OVA sensitization by intraperitoneal injection was used to induce airway inflammation in mice on days 0 and 7; then the mice were challenged using beclomethasone (150 µg/kg, inhalation), a standard anti-asthmatic drug, from day 14 to day 16. Furthermore, agmatine (200 mg/kg) was intraperitoneally injected on day 0 and then daily for 16 days, followed by OVA challenge. The lung weight ratio, total and differential cell counts, TNF-α, interleukin-5 (IL-5) and IL-13 in bronchoalveolar lavage fluid (BALF), lung nitrite/nitrate (NO), and oxidative parameters were determined. Moreover, histopathological and immunohistochemical staining was employed. RESULTS: Injection of agmatine (200 mg/kg) for 16 days significantly attenuated inflammation of the airways. The levels of BALF inflammatory cells, TNF-α, IL-5, IL-13, lung NO, and malondialdehyde (MDA), significantly decreased with concomitant elevation of superoxide dismutase (SOD) levels. Histological and immunohistochemical analyses of mast cells paralleled to biochemical improvements. CONCLUSION: Finally, this study illustrated that agmatine attenuates the allergic inflammation of airways caused by OVA by mitigating cytokines release, NO expression, and oxidative stress.
Assuntos
Agmatina , Antiasmáticos , Agmatina/farmacologia , Animais , Beclometasona , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Interleucina-13 , Interleucina-5 , Pulmão/metabolismo , Malondialdeído , Camundongos , Camundongos Endogâmicos BALB C , Nitratos , Nitritos , Ovalbumina , Superóxido Dismutase , Fator de Necrose Tumoral alfaRESUMO
Ulcerative colitis (UC) is an idiopathic chronic inflammatory disorder mainly affecting the colon and rectum. The present investigation was undertaken to evaluate the potential protective effect of flavocoxid, a dual COX and LOX inhibitor, in colitis model in rats. UC was induced by instillation of 2 ml of 4% acetic acid (AA) into the colon using a pediatric catheter in rats, and flavocoxid (10 and 20 mg·kg-1) was given once daily for 7 days before induction of colitis. Rats were sacrificed; sera were collected; colons and livers were isolated and then analyzed by biochemical, macroscopic, and histopathological examination. Pretreatment with flavocoxid (10 and 20 mg·kg-1) significantly reduced serum levels of alanine transaminase (ALT) (43.7 ± 7 and 76.2 ± 7.3 vs. 288.7 ± 31.4 in AA group) and aspartate transaminase (AST) (179.5 ± 22.2 and 200.5 ± 14 vs. 392.7 ± 35.6 in AA group) (p>0.05). Also, it decreased malondialdehyde (MDA) and nitric oxide (NOx) levels in both colonic and hepatic tissues. Moreover, flavocoxid effectively elevated colonic and hepatic reduced glutathione (GSH) level and superoxide dismutase (SOD) activity when compared to AA group (p>0.05). Additionally, flavocoxid significantly decreased levels of tumor necrosis factor-α (TNF-α) (878.2 ± 13.4 and 560.1 ± 2.9 vs. 1378.1 ± 31 in AA group) in colonic tissues and (701 ± 6.9 and 442.5 ± 8.2 vs. 1501 ± 9.4 in AA group) in hepatic tissues, nuclear factor kappa B (NF-κBp65) (493.8 ± 6.8 and 368.7 ± 3.1 vs. 659.2 ± 9.4 in AA group) in colonic tissues and (358 ± 5.1 and 163.5 ± 7.8 vs. 732.5 ± 4.5 in AA group) in hepatic tissues, myeloperoxidase (MPO) (15.7 ± 0.3 and 13 ± 0.2 vs. 20.9 ± 0.5 in AA group) in colonic tissues and (20.4 ± 0.3 and 16.3 ± 0.3 vs. 23.9 ± 1.2 in AA group) in hepatic tissues, and inducible nitric oxide synthase (iNOS) (12.5 ± 0.3 and 10 ± 0.2 vs. 16 ± 0.1 in AA group) in colonic tissues and (14.1 ± 0.04 and 11.5 ± 0.08 vs. 17.8 ± 0.1 in AA group) in hepatic tissues (p>0.05). Furthermore, it down-regulated Bax and caspase-3 expression in colonic and hepatic tissues upon comparison with AA group. Collectively, flavocoxid conferred a protective impact against acetic acid-induced colitis in rats via attenuating oxidative stress, inflammation, and apoptosis.
Assuntos
Catequina , Colite Ulcerativa , Ácido Acético , Animais , Catequina/uso terapêutico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Combinação de Medicamentos , Peroxidase , RatosRESUMO
Ulcerative colitis (UC) is a subcategory of intestinal inflammatory bowel disease characterized by up-regulation of proinflammatory cytokines and oxidative stress. The current study was designed to assess the probable protective effect of the nitric oxide (NO) donor, molsidomine, in experimental colitis model in rats. Rats were haphazardly classified into four groups: control, acetic acid, acetic acid + molsidomine (1 mg/kg) and acetic acid + molsidomine (2 mg/kg). Molsidomine (1 and 2 mg/kg/day) was administered by intra-peritoneal injection for 7 days prior to induction of UC. On the 8th day, colitis was induced by intra-rectal instillation of 2 ml of (4% v/v) acetic acid in normal saline using a pediatric plastic catheter. The rats were sacrificed 1 day following colitis induction, blood samples were obtained; colons and livers were isolated then underwent macroscopic, biochemical, histopathological and immunohistochemical examination. Pretreatment with molsidomine significantly reduced disease activity index, colon mass index, colonic macroscopic and histological damage. Besides, molsidomine significantly reduced the serum levels of alanine transaminase (ALT) (58.7 ± 8.9 & 59.7 ± 8 vs 288.75 ± 31.4 in AA group) and aspartate transaminase (AST) (196.2 ± 37.4 & 204 ± 30 vs 392.7 ± 35.6 in AA group). Moreover, molsidomine effectively decreased malondialdehyde (MDA) and total nitrate/nitrite (NOx) contents, and up regulated the enzymatic activity of superoxide dismutase (SOD) and glutathione level (GSH) in colonic and hepatic tissues. With regard to anti-inflammatory mechanisms, molsidomine suppressed tumor necrosis factor-alpha (TNF-α) (792.5 ± 16.7 & 448 ± 12.1 vs 1352.5 ± 45.8 in AA group) in colonic tissues and (701 ± 19 & 442.5 ± 22.5 vs 1501 ± 26 in AA group) in hepatic tissues as well as nuclear transcription factor kappa B (NF-kB/p65) levels (416.2 ± 4.1 & 185.5 ± 14.2 vs 659.2 ± 11.5 in AA group) in colonic tissues and (358 ± 6.2 & 163.5 ± 9.6 vs 732.5 ± 5.5 in AA group) in hepatic tissues. In addition, molsidomine significantly decreased inducible nitric oxide synthase (iNOS) levels (8.1 ± 0.1 & 4.9 ± 0.1 vs 16 ± 0.1 in AA group) in colonic tissues and (8.6 ± 0.3 & 6.1 ± 0.1 vs 17.8 ± 0.1 in AA group) in hepatic tissues, and myeloperoxidase (MPO) contents (10.5 ± 0.4 & 6.6 ± 0.3 vs 20.9 ± 0.6 in AA group) in colonic tissues and (13.1 ± 0.2 & 6.3 ± 0.06 vs 23.9 ± 1.4 in AA group) in hepatic tissues at p > 0.05. Furthermore, it suppressed apoptosis by reducing expression of Caspase 3 and Bax in colonic and hepatic tissues. Therefore, molsidomine might be a promising candidate for the treatment of UC.
Assuntos
Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Colite Ulcerativa/tratamento farmacológico , Inflamação/tratamento farmacológico , Molsidomina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ácido Acético , Alanina Transaminase/sangue , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Caspase 3/metabolismo , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Colo/patologia , Glutationa/metabolismo , Fígado/patologia , Masculino , NF-kappa B/metabolismo , Peroxidase/metabolismo , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Colon rectal cancer (CRC) is the second commonest malignancy in developed countries and a significant cause of mortality. Tenofovir reportedly reduces the risk of hepatocellular carcinoma and interferes with cell cycle and cell proliferation. The current study investigated the potential antitumor effect of tenofovir against experimentally induced CRC. CRC was induced by 1,2-dimethylhydrazine (DMH, 20 mg/kg, once a week) and high-fat diet (HFD) in Wistar rats. Rats received tenofovir at a dose of 25 or 50 mg/kg (i.p.) for 24 weeks. Tenofovir-25 failed to significantly decrease the total number of dysplasia, adenoma and adenocarcinoma and to improve histopathological changes; however, tenofovir-50 resulted in no tumors seen in the colon lumen and a significant decrease in the total number of dysplasia and no adenoma or adenocarcinoma observed compared to DMH/HFD group. Tenofovir-25 failed to attenuate DMH/HFD-induced cell proliferation, whereas tenofovir-50 significantly decreased cell proliferation revealed by the decreased PCNA expression. Tenofovir-25 also failed to attenuate DMH/HFD-induced oxidative stress, whereas tenofovir-50 significantly attenuated oxidative stress as indicated by the decreased MDA concentration and SOD activity along with the increased GSH concentrations. Moreover, tenofovir-50 decreased Bcl-2 and cyclin D1 expressions in colon tissues compared with DMH/HFD group. Tenofovir-50 also significantly decreased INF-ɤ concentration in colon tissues. These findings suggest that the high dose of tenofovir (50 mg/kg) has antitumor potential against DMH/HFD-induced CRC, which might be mediated through the inhibition of cell proliferation, oxidative stress, and inflammation.
Assuntos
Neoplasias do Colo , Inibidores da Transcriptase Reversa , Animais , Ratos , 1,2-Dimetilidrazina , Colo , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/tratamento farmacológico , Dieta Hiperlipídica , Ratos Wistar , Inibidores da Transcriptase Reversa/uso terapêutico , TenofovirRESUMO
Cisplatin is one of the most potent anti-cancer drugs used for the treatment of various solid tumors, yet it has several side effects that may limit its clinical use. Hepatotoxicity is one of the most serious side effects as it may lead to liver failure. Several mechanisms including oxidative stress, inflammation, and apoptosis have been examined in cisplatin-induced hepatotoxicity. Protocatechuic acid (Proto) which is naturally occurring phenolic acid has shown different biological activity as antioxidant, anti-inflammatory, and anti-apoptotic. In this study, we investigate the protective effect of Proto at two doses 100 and 150 mg/kg on hepatotoxicity induced by a single injection of 10 mg/kg cisplatin in female albino mice. The present study demonstrates for the first time that Proto administration (100 and 150 mg/Kg) significantly attenuates cisplatin-induced changes in liver function [increase serum albumin and decrease liver injury markers ALT, AST, GGT, and bilirubin]. This was associated with marked hepatic antioxidant effects [decrease MDA and NO levels, increase GSH and SOD activity]. Moreover, Proto reduced cisplatin-induced apoptosis in the liver through decreasing caspase-3, annexin-V, and BAX. Both doses suppressed cisplatin-induced expression of iNOS and NF-á´B p65 subunit and pro-inflammatory cytokines (IL-6 and TNF-α). Also, Proto improved histopathological examination of the liver. The present findings reveal that the antioxidant, anti-inflammatory, and anti-apoptotic effects of Proto are the main mechanisms by which Proto can ameliorate cisplatin-induced liver injury.
Assuntos
Cisplatino/efeitos adversos , Hidroxibenzoatos/farmacologia , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cisplatino/farmacologia , Cisplatino/toxicidade , Citocinas/metabolismo , Feminino , Hidroxibenzoatos/metabolismo , Fígado/metabolismo , Camundongos , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacosRESUMO
This work explored influences of protocatechuic acid (PCA) on type 2 diabetes (T2D)-associated hepatic insulin resistance and other metabolic, hepatic and vascular irregularities using the rat model of high fat diet (HFD)+high fructose+low dose streptozotocin (STZ). Twenty-four male Wister rats were used. Twelve rats were ad libitum supplied with HFD and high fructose drinking water (25 % w/v) for 60 days. On day 30, they received a single injection of STZ (35 mg/kg, i.p). On day 32, they were divided into two subgroups (n = 6/each): T2D + PCA, received PCA (100 mg/kg/day, orally) and T2D, received PCA vehicle till the end of experiment. Rats provided with regular diet and fructose-free drinking water, with or without PCA treatment, served as PCA and control groups (n = 6/each), respectively. PCA treatment significantly reduced the elevated levels of fasting glycemia and insulin, AUCOGTT, AUCITT, and HOMA-IR index, while it boosted HOMA-ß and insulinogenic index values in T2D rats. PCA ameliorated serum lipid levels and hepatic function parameters and mitigated hepatosteatosis in T2D rats. Mechanistically, PCA mitigated hepatic lipid peroxidation and restored reduced glutathione (GSH) and superoxide dismutase (SOD) to near-normal levels. Moreover, PCA enhanced hepatic protein levels of P-AKTser473 and hepatic mRNA expression of insulin receptor substrate 1 (IRS1), phosphatidylinositol 3 kinase (PI3K)-p85 and AKT2. Furthermore, PCA ameliorated aortic oxidative stress in T2D rats, possibly via reducing serum levels of advanced glycation end products (AGEs) and diminishing vascular expression of RAGE and NOX4 mRNA. Collectively, PCA may improve hepatic insulin resistance and vascular oxidative status by modulating IRS1/PI3K/AKT2 and AGE-RAGE-NOX4 pathways, respectively.
Assuntos
Aorta Torácica/efeitos dos fármacos , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Hidroxibenzoatos/farmacologia , Resistência à Insulina , Fígado/efeitos dos fármacos , Animais , Aorta Torácica/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Produtos Finais de Glicação Avançada/sangue , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/genética , Fígado/metabolismo , Masculino , NADPH Oxidase 4/genética , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Ratos Wistar , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Hepatic damage is one of the most common complications related to cisplatin (Cis) use. Recently, liver protection lines are being discovered to avoid hepatic cell death as a result of oxidative, inflammatory, and apoptotic disturbance. Limited data reported the hepatoprotective effect of vinpocetine (Vin) in acute liver injury models. This study was designed to determine the potential protective effect of Vin (10-30 mg/kg, orally) against Cis-induced liver injury (10 mg/kg, IP) in mice. Vin administration for 1 week before Cis injection until the end of the experiment. On the 6th day after Cis injection, mice were anesthetized, blood and tissue samples were collected. Hepatic function, histological changes, oxidative stress, inflammation, and apoptotic markers were investigated. Vin administration ameliorated liver injury as indicated by decreased liver injury parameters; serum aminotransferases, ALK-P, GGT, and bilirubin, restored the anti-oxidant status by decrease MDA and NOx , and increased GSH and SOD, inhibited inflammation (IL-6, TNF-α, NFκB-p65, and iNOS) and apoptosis (Annexin-V, Bax, and Caspase-3) parameters. Vin confers dose-dependent protection against Cis-induced liver injury. The hepatoprotective effect of Vin involved anti-oxidative, anti-inflammatory, and anti-apoptotic activities.
Assuntos
Anexina A5/metabolismo , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Cisplatino/toxicidade , Fígado/efeitos dos fármacos , Alcaloides de Vinca/farmacologia , Proteína X Associada a bcl-2/metabolismo , Animais , Biomarcadores/sangue , Peso Corporal/efeitos dos fármacos , Feminino , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Tamanho do Órgão/efeitos dos fármacosRESUMO
Protocatechuic acid (PCA), the natural phenolic antioxidant, reportedly exhibited hypoglycemic and insulin-like effects. Recent studies have reported its cardioprotective effect in glucocorticoid (GC)-induced hypertensive rats. Nevertheless, its beneficial role has not been investigated in the setting of GCs excess-induced insulin resistance. This study aimed to investigate the possible protective potential and the plausible mechanisms of pretreatment with PCA against GCs-induced insulin resistance, liver steatosis and vascular dysfunction. Insulin resistance was induced in male Wistar rats by a 7-day treatment with dexamethasone (DEX) (1â¯mg/kg/day, i.p.). PCA (50, 100â¯mg/kg/day, orally) was started 7 days before DEX administration and continued during the test period. PCA significantly and dose-dependently attenuated DEX-induced a) glucose intolerance (↓ AUCOGTT), b) hyperglycemia (↓ fasting blood glucose), c) impaired insulin sensitivity [↓fasting plasma insulin and homeostasis model assessment of insulin resistance (HOMA-IR) index)] and d) dyslipidemia (↓total cholesterol, triglycerides, low-density lipoprotein-cholesterol and very low-density lipoprotein-cholesterol). PCA mitigated DEX-induced liver steatosis with associated reduction in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity. Moreover, PCA ameliorated DEX-induced vascular dysfunction and enhanced ACh-induced relaxation in aortic rings. The metabolic ameliorating effects of PCA might be attributed to the enhanced insulin signaling in soleus muscles (↑AKT phosphorylation) and mitigating gluconeogenesis (↓ hepatic mRNA expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). The vasculoprotective effect of PCA might be related to its ability to restore normal mRNA expression of [endothelial nitric oxide synthase (eNOS) and NADPH Oxidase 4 (NOX4)]. PCA restored normal oxidative balance [↓ oxidant species, malondialdehyde (MDA) and (↑ antioxidant superoxide dismutase (SOD)]. The findings herein reveal for the first time that PCA may be taken as a supplement with GCs to limit their metabolic and vascular side effects through its hypoglycemic, insulin-sensitizing, hypolipidemic and antioxidant effects.
Assuntos
Antioxidantes , Cardiotônicos , Hidroxibenzoatos , Hipoglicemiantes , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Cardiotônicos/administração & dosagem , Cardiotônicos/farmacologia , Suplementos Nutricionais , Modelos Animais de Doenças , Dislipidemias/tratamento farmacológico , Fígado Gorduroso/tratamento farmacológico , Intolerância à Glucose/tratamento farmacológico , Hidroxibenzoatos/administração & dosagem , Hidroxibenzoatos/farmacologia , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Resistência à Insulina , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Amongst the various forms of lung injury; pulmonary fibrosis remains the most intricate form with limited therapeutic options to both the patient and the physicians. Bleomycin (BLM) is a chemotherapeutic agent used for the treatment of various carcinomas; however, its therapeutic value is significantly limited by its associated pulmonary fibrosis. The current study highlights the prominent antioxidant, anti-inflammatory and anti-fibrotic effect of crocin against BLM-induced pulmonary fibrosis. Intratracheal BLM instillation induced significant biochemical, structural, functional and vascular pulmonary injury. BLM instillation increased oxidant load with quenching of antioxidant defenses together with increase inflammatory and fibrotic cytokines expression. Crocin significantly attenuated BLM-induced lung injury and its effect was comparable to the standard anti-fibrotic; halofuginone. The observed anti-inflammatory and anti-fibrotic and antioxidant impacts are thought to be embroiled in the therapeutic impacts of crocin. Down-regulation of TLR4, IL-10 expression is the major pathway involved in the observed anti-inflammatory effects and finally, down-regulation of tissue expression of TNF-α and TGF-ß1 is the major pathways implicated in the observed anti-fibrotic activities and modulation of Nrf2 and HO-1 pathways is the main mechanism involved in the observed antioxidant effects.
Assuntos
Bleomicina/toxicidade , Carotenoides/farmacologia , Pneumonia/prevenção & controle , Artéria Pulmonar/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , Doenças Vasculares/prevenção & controle , Animais , Antibióticos Antineoplásicos , Masculino , Pneumonia/induzido quimicamente , Pneumonia/patologia , Artéria Pulmonar/patologia , Fibrose Pulmonar/complicações , Fibrose Pulmonar/patologia , Ratos , Ratos Sprague-Dawley , Doenças Vasculares/induzido quimicamente , Doenças Vasculares/patologiaRESUMO
Type 2 diabetes mellitus (T2D) is a chronic metabolic disorder considered to be the most predominant form of diabetes throughout the world. This study aimed to investigate the possible effects of cinnamaldehyde (CIN) on insulin signaling pathways in STZ-induced T2D rat model. T2D was originated by feeding rats with a high-fat diet (HFD) plus 25% fructose solution plus streptozotocin (STZ) (35 mg/kg, i.p.). CIN effects were investigated on fasting blood glucose, insulin, oral glucose tolerance test (OGTT), insulin tolerance test (ITT), liver biomarkers, lipid profile, oxidative stress biomarkers, serum advanced glycation end products (AGEs) and its receptors (RAGE) in the aorta, and histopathology of the liver and aorta. Additionally, the mRNA expression of hepatic insulin signaling pathway genes, phosphorylated AKT (serine 473) (P-AKT ser473) level, and aortic nitric oxide synthase3 (eNOS) and NADPH oxidase4 (NOX4) were determined. CIN treatment for 30 days significantly decreased OGTT, ITT, fasting blood glucose, insulin, and HOMA-IR and increased HOMA-ß index when compared to diabetic rats. CIN also improved lipid profile and decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity, serum AGEs, and aortic RAGE. Additionally, CIN treatment significantly decreased hepatic malondialdehyde (MDA), increased hepatic and aortic glutathione (GSH) and superoxide dismutase (SOD), and decreased steatosis and inflammation observed in liver tissue of rats. Additionally, significant elevation in mRNA expression of insulin receptor substrate1 (IRS1), phosphatidylinositol 3-kinase regulatory subunit1 (PI3K-P85 subunit), and AKT serine/threonine kinase2 (AKT2); increased levels of P-AKT ser473 and aortic eNOS; and decrease in mRNA expression of NOX4 were detected in CIN-treated group when compared to diabetic group. This study suggests antidiabetic and antioxidant effects of CIN probably through upregulation of eNOS and IRS1/PI3K/AKT2 signaling pathway and alleviating AGEs, RAGE, and NOX4 elevation.