RESUMO
The current study investigates the anti-inflammatory and hepatoprotective effects of selenium (Se) formulated as nanoparticles (SeNPs) and in combination with quercetin (QCT) against thioacetamide (TAA)-induced hepatocellular carcinoma (HCC) in rats. ââââââSeventy-two male Sprague-Dawley rats were divided into six groups (n = 12). Three control groups; normal, SeNPs; group received SeNPs only and HCC; group received TAA. In addition, three preventive groups; SeNPs + TAA, QCT + TAA, and QCT + SeNPs + TAA. Induction of HCC was detected histopathologically and by the raise of the serum level of alpha-fetoprotein (AFP). Oxidative stress was evaluated by the hepatic levels of reduced glutathione (GSH), glutathione peroxidase (GPx), and malondialdehyde (MDA) spectrophotometrically. The oncogenic pathway of p53/ß-catenin/cyclin D1 was assessed by immunohistochemistry. The inflammatory markers; interleukin-33 (IL-33), IL-6, and IL-1ß were assessed by enzyme-linked immune sorbent assay. SeNPs prevented the elevation of serum AFP and hepatic IL-33, IL-1ß, and IL-6 in comparison to HCC or QCT + TAA groups. SeNPs + TAA exhibited a lower positive hepatic staining of p53, ß-catenin, and cyclin D1 in comparison to HCC or QCT + TAA groups. Moreover, SeNPs improved the overall oxidative balance indicated by low hepatic MDA and enhanced GSH and GPx when compared to HCC or QCT + TAA groups. ââSeNPs alone and in combination with QCT were found to suppress the progression of HCC in rats via the enhancement of the oxidative stress and then inflammatory status and the prevention of the deregulation of the oncogenic axis pathway of p53/ß-catenin/cyclin D.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Selênio , Animais , Carcinoma Hepatocelular/metabolismo , Ciclina D1/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-33/metabolismo , Interleucina-33/farmacologia , Interleucina-6/metabolismo , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Masculino , Estresse Oxidativo , Quercetina/farmacologia , Ratos , Ratos Sprague-Dawley , Selênio/farmacologia , Tioacetamida/toxicidade , Proteína Supressora de Tumor p53/metabolismo , alfa-Fetoproteínas , beta Catenina/metabolismoRESUMO
Breast cancer is a leading cause of death. Anticancer treatment such as gold nanoparticles (AuNP) seems highly promising in this regard. Therefore, this study aimed to assess the beneficial effect of doxorubicin (Dox) and polydatin (PD) AuNP in Ehrlich ascites carcinoma (EAC) and the ability of PD-AuNP to protect the heart from Dox's deteriorating effects. EAC was induced in mice. The mice were divided into nine groups: normal, EAC, PD: received PD (20 mg/kg), Dox: received Dox (2 mg/kg), PD-AuNPH: received 10 ppm AuNP of PD, PD-AuNPL: received 5 ppm AuNP of PD, Dox-AuNP: received Dox-AuNP, PD-Dox-AuNP: received PD-Dox-AuNP, AuNP: received AuNP. On the 21st day from tumor inoculation, the mice were sacrificed and tumor and heart tissues were removed. Tumor ß-catenin/Cyclin D1 and p53 were assessed by immunohistochemistry. IL-6 was determined by enzyme-linked immunosorbent assay. PD-AuNP and Dox-AuNP showed a significant reduction in tumor volume and weight more than their free forms. Also, PD-AuNP and Dox-AuNP showed markedly less dense tumor cells. ß-catenin and Cyclin D1 were markedly decreased and p53 was highly upregulated by PD-AuNP and Dox-AuNP. Moreover, PD-AuNP and Dox-AuNP have the ability to decrease IL-6 production. PD-AuNP protected the heart from Dox-induced severe degeneration. Therefore, PD-AuNP could be a tool to decelerate the progression of breast cancer.
Assuntos
Antineoplásicos/administração & dosagem , Carcinoma de Ehrlich/tratamento farmacológico , Doxorrubicina/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Fallopia japonica/química , Glucosídeos/administração & dosagem , Ouro/química , Nanopartículas Metálicas/química , Sistemas de Liberação de Fármacos por Nanopartículas/química , Compostos Fitoquímicos/administração & dosagem , Fitoterapia/métodos , Substâncias Protetoras/administração & dosagem , Estilbenos/administração & dosagem , Animais , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Coração/efeitos dos fármacos , Camundongos , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacosRESUMO
BACKGROUND: Monosodium glutamate was considered one of the food additive and flavor enhancer in processed meat and soup that affects testicular tissues, the aim of this research to investigates the impact of monosodium glutamate (MSG) on testicular structure in rats and explores the potential protective effects of resveratrol. MATERIAL AND METHODS: Four experimental groups involved in our study 10 rats of each.: the first group as control group; the second group (Resveratrol group: control rats received 20 mg/kg of resveratrol, via oral gavage); the third group (MSG group: rats received monosodium glutamate (MSG) with a dose 60 mg/kg body weight daily, via gastric tube, and the fourth group (MSG+ Resveratrol group). Serum level of testosterone, FSH, LH, were measured. Testicular tissues were prepared for measurement of oxidative stress markers, and gene expression of NLRP3, Caspase 3, and GSK-3ß. Moreover, paraffin blocks contained testicular tissue used for histological and immunohistochemical examination. Additionally, seminal smear from epididymis were examined. RESULTS: MSG administration adversely affected testosterone production, hormonal levels, and sperm parameters, Histological examination revealed marked testicular degeneration, and oxidative stress assessments indicated elevated level of MDA a lipid peroxidation marker and decrease in SOD, CAT antioxidant enzymes. Moreover, MSG-induced apoptotic and pyroptotic markers and its gene expressions. Importantly. Administration of resveratrol reversed the detrimental effects of MSG, demonstrating its corrective influence on the hypothalamic-pituitary-gonadal axis disruption, improvement of sperm parameters, attenuation of oxidative stress, anti-apoptotic activity, and anti-pyroptotic effects. The expression of Ki-67 as a cell proliferation marker further supported the positive response to spermatogenesis dysfunction upon resveratrol treatment. CONCLUSIONS: This comprehensive exploration sheds light on the protective effect of resveratrol against MSG-induced testicular with exploration of its mechanistic role.
RESUMO
Cisplatin (CIS) is a potent anticancer drug that is used in the treatment of different types of cancer. Owing to its serious side effects, its clinical use is considerably limited. AIMS: This study was mapped to investigate the potential effects of desloratadine (DES) against CIS-induced nephrotoxicity and testicular injury. MAIN METHODS: DES (5 and 10 mg/kg) was orally administered for 10 days, and CIS was injected once (10 mg/kg, i.p.) in adult male rats on day 9 to induce both renal and testicular toxicity. KEY FINDINGS: DES significantly attenuated CIS-induced alterations in histopathology and biomarkers. DES resulted in a significant reduction in serum levels of creatinine (Cr), urea, and blood urea nitrogen (BUN), in addition to a marked decrease in urinary levels of albumin and total protein. Additionally, DES efficiently reinstated the oxidative balance by preventing the elevation of malondialdehyde (MDA) and enhancing superoxide dismutase (SOD) activity, and increasing glutathione (GSH) levels. Moreover, DES produced a profound decrease in renal and testicular levels of nucleotide-binding domain-(NOD) like receptor 3 (NLRP3), interleukin (IL)-1ß, and caspase-1 when compared to the CIS group. Furthermore, DES significantly decreased CIS-induced elevation in toll-like receptor 4 (TLR4), tumor necrosis factor-alpha (TNF-α), and nuclear factor-kappa B (NF-κB) levels in both renal and testicular tissues. SIGNIFICANCE: DES can be used as adjuvant therapy with CIS in cancerous cases, pending further clinical studies.
Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos , Masculino , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Cisplatino/toxicidade , Receptor 4 Toll-Like/metabolismo , Estresse Oxidativo , Transdução de Sinais , NF-kappa B/metabolismo , Glutationa/metabolismoRESUMO
Fisetin (FST) is a naturally occurring flavonol that has recently emerged as a bioactive phytochemical with an impressive array of biological activities. To the author knowledge, boosting the activity of FST against severe acute pancreatitis (SAP) through a nanostructured delivery system (Nanophytomedicine) has not been achieved before. Thereupon, FST-loaded lipid polymer hybrid nanoparticles (FST-loaded LPHNPs) were prepared through conjoined ultrasonication and double emulsion (w/o/w) techniques. Comprehensive in vitro and in vivo evaluations were conducted. The optimized nanoparticle formula displayed a high entrapment efficiency % of 61.76 ± 1.254%, high loading capacity % of 32.18 ± 0.734, low particle size of 125.39 ± 0.924 nm, low particle size distribution of 0.357 ± 0.012, high zeta potential of + 30.16 ± 1.416 mV, and high mucoadhesive strength of 35.64 ± 0.548%. In addition, it exhibited a sustained in vitro release pattern of FST. In the in vivo study, oral pre-treatment of FST-loaded LPHNPs protected against L-arginine induced SAP and multiple organ injuries in rats compared to both FST alone and plain LPHNPs, as well as the untreated group, proven by both biochemical studies, that included both amylase and lipase activities, and histochemical studies of pancreas, liver, kidney and lungs. Therefore, the study could conclude the potential efficacy of the novel phytopharmaceutical delivery system of FST as a prophylactic regimen for SAP and consequently, associated multiple organ injuries.
Assuntos
Nanopartículas , Pancreatite , Ratos , Animais , Polímeros , Doença Aguda , Lipídeos , Liberação Controlada de Fármacos , Flavonóis , Compostos Fitoquímicos , Tamanho da Partícula , Portadores de FármacosRESUMO
Background: Hyperglycemia usually impairs wound healing by dysregulating the inflammatory response and angiogenesis. This study aimed to examine the synergistic effect of dapagliflozin and Zamzam water (ZW) on the healing of diabetic wounds and to explore their anti-inflammatory and proangiogenic effects.Materials and methods: A full-thickness excisional wound was made on the backs of all groups after two weeks of diabetes induction. Forty rats were divided into five groups, with eight rats per group; Group 1: Control non-diabetic rats; Group II: Untreated diabetic rats; Group III: Diabetic rats drinking ZW; Group IV: Diabetic rats receiving an oral dose of 1 mg/kg dapagliflozin; and Group V: Received both dapagliflozin and ZW. The healing of diabetic wounds was assessed by measuring wound closure, oxidative stress markers, immunohistochemical staining of NF-ßB, VEGF, CD34, CD45, Ki-67, and eNOS, gene expression of MMP-9, TGF-ß1, EGF-b1, FGF, and Col1A1, protein levels of TNFα, IL-1ß, IL6, Ang II, and HIF-1α by ELISA assay, and histological examination with H & E and Masson's trichrome. Combined treatment with dapagliflozin and ZW significantly (p < 0.05) enhanced the wound closure and antioxidant enzyme level, with apparent histological improvement, and shortened the inflammatory stage of the diabetic wound by decreasing the level of inflammatory markers NF-κB, TNF-α, IL-1ß, IL6, and CD45. Therefore, it improved angiogenesis markers VEGF, CD34, eNOS, EGF-ß1, FGF, Ang II, and HIF-1α, increasing Ki-67 cellular proliferation. Moreover, it enhanced the remodeling stage by increasing MMP-2, TGF-ß1, and Col1A1 levels compared to diabetic rats.
Assuntos
Diabetes Mellitus Experimental , Fator de Crescimento Transformador beta1 , Ratos , Animais , Fator de Crescimento Transformador beta1/farmacologia , Fator de Crescimento Transformador beta1/uso terapêutico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator de Crescimento Epidérmico/farmacologia , Fator de Crescimento Epidérmico/uso terapêutico , Interleucina-6 , Antígeno Ki-67 , Cicatrização , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Fator de Necrose Tumoral alfaRESUMO
Diabetic nephropathy (DN) is a renal complication of diabetic hyperglycemia. The Signal transducer and activator of transcription 3 (Stat3) is a center molecule of the chronic inflammation causing DN progression. Therefore, the study investigated the possible inhibitory effects of Rutin (Ru) and Selenium (Se), formulated as nanoparticles (SeNPs), on Stat3 pathway in streptozotocin (STZ)-induced DN in Sprague-Dawley rats. Ru (100 mg/kg/orally) and SeNPs (equivalent to 5 mg of Se/kg/orally) were given as treatment for eight weeks. An assessment of fasting blood glucose, renal function biomarkers, GSH, and MDA was carried out spectrophotometrically. ELISA assessment of renal IL-6, NF-κB, TNF-α, Jak-2, and p-Stat3 was performed. Sirt-1, Nrf-2, and HO-1 were assessed immunohistochemically. DN group receiving Ru + SeNPs showed a decrease in fasting blood glucose, serum creatinine, and urea (163.8 ± 22.8, 0.54 ± 0.1, and 53.6 ± 25.7 mg/dl, respectively), compared to the DN group (443.8 ± 42.72, 1.58 ± 0.4, and 281.8 ± 47.35 mg/dl, respectively). In addition, it exhibited elevation in the levels of Sirt-1, Nrf-2 and HO-1 compared to the DN group. Finally, Ru + SeNPs exhibited a significant reduction in IL-6, NF-κB, TNF-α, Jak-2, and p-Stat3 (42.8 ± 10.3, 1.2 ± 0.1, 53.4 ± 3.87, 0.8 ± 0.06 and 1.1 ± 0.2 U/g tissue, respectively) when compared to the DN group (155.3 ± 13.97, 2.8 ± 0.3, 105.5 ± 32.84, 2.03 ± 0.2 and 2.56 ± 0.15 U/g tissue, respectively). Therefore, combining Ru with SeNPs has a potential renoprotective effect against DN by upregulating Nrf-2/HO-1 and downregulating Jak-2/Stat3 Pathways.
Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Nanopartículas , Selênio , Sirtuínas , Animais , Biomarcadores , Glicemia/análise , Creatinina , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Interleucina-6/metabolismo , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Rutina/farmacologia , Rutina/uso terapêutico , Fator de Transcrição STAT3/metabolismo , Selênio/farmacologia , Selênio/uso terapêutico , Transdução de Sinais , Sirtuínas/metabolismo , Estreptozocina/efeitos adversos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
AIMS: Montelukast, a selective antagonist of type 1 cysteinyl-leukotriene receptors, has antioxidant and anti-inflammatory abilities. This study aimed to explore its hepatoprotective impact against CCl4-induced hepatotoxicity compared to a standard hepatoprotective agent, silymarin. MAIN METHODS: Twenty-four albino mice were used in this study, CCl4 (1 mL/kg of 1:1 v/v CCl4:olive oil) was singly injected in mice, and montelukast was administered in a dose of 10 mg/kg. KEY FINDINGS: Results revealed that montelukast significantly improved CCl4-induced alterations in both structure and function of the liver, verified respectively through histopathology and by the reduced levels of ALT, AST, ALP, and GGT upon comparison with CCl4. Also, montelukast prevented the induction of oxidative stress via decreasing hepatic MDA content and enhancing GSH levels. Moreover, montelukast produced a profound decrease in the levels of hepatic NLRP3 and its adaptor protein, ASC, and a reduction in the pro-inflammatory markers, NF-κB, IL-1ß, TNF-α, and IL-6. In addition, montelukast markedly reduced liver fibrosis, as illustrated by Masson Trichrome, and the decreased hepatic levels of TGF-ß and α-SMA. Furthermore, montelukast efficiently decreased apoptosis as manifested by the decreased hepatic level of Caspase 3. SIGNIFICANCE: Montelukast protected against CCl4-induced hepatotoxicity via exerting antioxidant, anti-inflammatory, anti-fibrotic, and anti-apoptotic effects.
Assuntos
Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas , Acetatos , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Ciclopropanos , Inflamassomos/metabolismo , Fígado/metabolismo , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo , Quinolinas , SulfetosRESUMO
Doxorubicin (Dox) is an indispensable chemotherapeutic agent associated with damaging cardiotoxicity. Baicalin (BA) is a flavonoid, extracted from the medicinal plant Scutellariae baicalensis Georgi. BA is well known for its anti-inflammatory and antioxidant effects. Our study investigated the potential effect of BA in attenuating Dox-induced cardiotoxicity. To this end, male Swiss albino mice were given BA (100 mg/kg/d, orally) for 4 wk and were challenged with Dox (six intraperitoneal doses, each 2.5 mg/kg, every other day with a final cumulative dose of 15 mg/kg). Serum activities of cardiac biomarkers (cardiac troponin-I, creatine kinase-membrane bound, lactate dehydrogenase, and aspartate aminotransferase) were assessed along with the histopathological examination of the heart tissues. Gene expression of Toll-like receptor 4 (TLR4) was analyzed by quantitative reverse transcription real-time polymerase chain reaction. Analysis of the protein levels of ß-catenin and nuclear factor-κB (NF-κB) was done immunohistochemically. Cardiac Dickkopf-1 (DKK1) and interleukin-1beta (IL-1ß) were quantified by enzyme-linked immuno-sorbent assay. Cardiac levels of reduced glutathione (GSH) and malondialdehyde (MDA) were detected spectrophotometrically. Pretreatment with BA significantly prevented Dox-induced elevation of serum activities of cardiac biomarkers and alterations to the heart. Moreover, BA suppressed the gene overexpression of cardiac TLR4 and subsequently prevented Dox-induced elevation of both cardiac NF-κB and IL-1ß. BA also significantly reduced the cardiac levels of DKK1 and elevated the level of ß-catenin. Dox-induced elevation of MDA and reduction of GSH were reversed by BA. BA exhibited a novel cardioprotective effect against Dox-induced cardiotoxicity. The cardioprotective effect was indicated through the inhibition of the inflammatory TLR4/NF-κB pathway and the activation of the protective Wnt/ß-catenin pathway by the suppression of DKK1.
Assuntos
Cardiotoxicidade , NF-kappa B , Animais , Antibióticos Antineoplásicos/metabolismo , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/uso terapêutico , Antioxidantes/uso terapêutico , Biomarcadores/metabolismo , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/etiologia , Cardiotoxicidade/prevenção & controle , Doxorrubicina/metabolismo , Doxorrubicina/toxicidade , Flavonoides/farmacologia , Camundongos , Miocárdio/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , beta Catenina/metabolismoRESUMO
AIM: Liver cirrhosis is the result of a vicious cycle of both chronic oxidative stress and inflammation. NADPH oxidase-4 (NOX4) and its companion, NOD-like receptor protein 3 (NLRP3) inflammasome, are emerging as therapeutic targets of liver fibrosis. MAIN METHODS: Baicalin (BA), a natural flavone, has been investigated for its therapeutic potential against cirrhosis induced by thioacetamide (TAA) (200 mg/kg, twice/week) for 12 weeks in Sprague-Dawley rats. Two doses of BA were administered (25 and 75 mg/kg/day, orally, a week after TAA was stopped and continued for 4 weeks). KEY FINDINGS: BA was able to reduce fibrosis visualized by Masson trichrome and immunohistochemical staining of the hepatic α-smooth muscle actin (α-SMA) and transforming growth factor-ß1. Moreover, BA was able to ameliorate inflammation by reducing hepatic NLRP3 inflammasome subunits, NLRP3 and caspase-1, both parts of the complex responsible for the activation of different interleukins (IL), measured as IL-1ß. In addition, BA was able to reduce hepatic nuclear factor kappa B (NF-κB)-driven inflammation through IL-6. BA targeted inflammation through its anti-oxidant ability evidenced by the enhancement of the hepatic superoxide dismutase (SOD) and reduced glutathione (GSH) activity and level, respectively, and the reduction of both hepatic malondialdehyde (MDA) and nitric oxide (NOx) contents. Treatment with BA significantly decreased TAA-induced elevation in hepatic NOX4, a key enzyme for reactive oxygen species (ROS) generation, as well as, inducible nitric oxide synthase (iNOS). SIGNIFICANCE: therefore, the study could conclude, the anti-fibrotic effect of BA through TGF- ß1/NOX4/NF-κB/NLRP3 pathway, exerting both anti-inflammatory and anti-oxidant effects.
Assuntos
Flavonoides/farmacologia , Inflamassomos/metabolismo , Cirrose Hepática/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Fibrose/induzido quimicamente , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Flavonoides/metabolismo , Inflamação/patologia , Fígado/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Masculino , NADPH Oxidase 4/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tioacetamida/efeitos adversos , Tioacetamida/farmacologiaRESUMO
Allantoin (ALL) is a phytochemical possessing an impressive array of biological activities. Nonetheless, developing a nanostructured delivery system targeted to augment the gastric antiulcerogenic activity of ALL has not been so far investigated. Consequently, in this survey, ALL-loaded chitosan/sodium tripolyphosphate nanoparticles (ALL-loaded CS/STPP NPs) were prepared by ionotropic gelation technique and thoroughly characterized. A full 24 factorial design was adopted using four independently controlled parameters (ICPs). Comprehensive characterization, in vitro evaluations as well as antiulcerogenic activity study against ethanol-induced gastric ulcer in rats of the optimized NPs formula were conducted. The optimized NPs formula, (CS (1.5% w/v), STPP (0.3% w/v), CS:STPP volume ratio (5:1), ALL amount (13 mg)), was the most convenient one with drug content of 6.26 mg, drug entrapment efficiency % of 48.12%, particle size of 508.3 nm, polydispersity index 0.29 and ζ-potential of + 35.70 mV. It displayed a sustained in vitro release profile and mucoadhesive strength of 45.55%. ALL-loaded CS/STPP NPs (F-9) provoked remarkable antiulcerogenic activity against ethanol-induced gastric ulceration in rats, which was accentuated by histopathological, immunohistochemical (IHC) and biochemical studies. In conclusion, the prepared ALL-loaded CS/STPP NPs could be presented to the phytomedicine field as an auspicious oral delivery system for gastric ulceration management.
Assuntos
Alantoína/uso terapêutico , Quitosana/química , Composição de Medicamentos , Nanopartículas/química , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Adesividade , Alantoína/química , Alantoína/farmacologia , Animais , Quitosana/análogos & derivados , Liberação Controlada de Fármacos , Etanol , Mucosa Gástrica/patologia , Mediadores da Inflamação/sangue , Cinética , Malondialdeído/metabolismo , Mucinas/metabolismo , Fator 2 Relacionado a NF-E2 , Nanopartículas/ultraestrutura , Estresse Oxidativo , Tamanho da Partícula , Difração de Pó , Ratos , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática , Úlcera Gástrica/sangue , Úlcera Gástrica/patologia , Temperatura , Fator de Necrose Tumoral alfa/metabolismoRESUMO
AIMS: Wnt3a and Wnt5a are ligands orchestrating the canonical and non-canonical pathways, respectively, with involvement in hepatocellular carcinoma (HCC). Hesperidin (HP) is a natural product found in citrus fruits and reputed for its antitumor activity. The present study aims to investigate the potential hepatoprotective effect of HP against thioacetamide (TAA)-induced HCC focusing on its potential role on Wnt3a and Wnt5a signaling pathways. MAIN METHODS: Forty rats were equally divided into groups; normal control, HP control (receiving HP, 150mg/kg/day), HCC (receiving TAA, 200mg/kg twice weekly for 14weeks) and HP-HCC (receiving HP and TAA). Gene expressions of Wnt3a, Wnt5a, ß-catenin and Cyclin D1 were assessed by qPCR, while their protein levels, along with active caspase-3 level, were quantified by ELISA and immunohistochemistry. Liver functions, oxidative stress parameters and myeloperoxidase activity were measured. MTT assay of hepG2 cells treated with recombinant Wnt3a (10ng/ml) in presence or absence of HP (100µM) was performed. KEY FINDINGS: HCC group exhibited a significant increase in Wnt3a, ß-catenin, Cyclin D1 and Wnt5a gene expressions, as well as, their protein levels. HP significantly prevented TAA-activated Wnt3a/ß-catenin and Wnt5a pathways. Moreover, HP exerted hepatoprotective effect by significantly improving the oxidative imbalance, inflammation and liver function parameters, serum ALT, AST activities, and albumin level. SIGNIFICANCE: Our study is the first to report the possible role of Wnt3a/ß-catenin and Wnt5a pathways in TAA-induced early HCC model in rats. HP has a prophylactic effect against hepatocarcinogenesis via preventing the induction of both canonical and non-canonical Wnt pathways.
Assuntos
Carcinoma Hepatocelular/prevenção & controle , Hesperidina/farmacologia , Neoplasias Hepáticas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Tioacetamida/toxicidade , Proteína Wnt-5a/metabolismo , Proteína Wnt3A/metabolismoRESUMO
In Egypt, hepatocellular carcinoma (HCC) was predicted to continue to rise over the next few decades causing a national problem. Meanwhile, glypican-3 (GPC3), a highly expressed glypican, has emerged as a potential target for HCC immunotherapy. Therefore, we aimed to identify the impact of blocking GPC3 on liver damage in HCC as well as a possible mechanism. Fifty four HCC patients, 20 cirrhotic patients and 10 healthy subjects were recruited. Serum levels of GPC3, sulfatase-2 (SULF-2), heparan sulfate proteoglycan (HSPG), insulin-like growth factor-II (IGF-II) were measured by ELISA. In parallel, HCC was induced in 40 male Sprague-Dawley rats in presence/absence of antiGPC-3. Liver impairment was detected by investigating liver sections stained with hematoxylin/eosin and serum α-fetoprotein (AFP). Liver homogenates of GPC3, SULF-2, and HSPG were measured by ELISA. Gene expression of caspase-3 and IGF-II were assayed by RT-PCR. HCC patients showed significant elevated serum levels of GPC3, IGF-II and SULF-2 accompanied by decreased HSPG. However, treatment of HCC rats with antiGPC-3 significantly reduced serum AFP and showed nearly normal hepatocytes. In addition, antiGPC-3 significantly reduced elevated liver homogenates protein levels of GPC3 and SULF-2 and gene expression of IGF-II and caspase-3. antiGPC-3 restored the reduced hepatic HSPG. antiGPC-3 showed anti-tumor activity as well as hepatoprotective effects. antiGPC-3-chemoprotective effect can be explained by forced reduction of IGF-II expression, restoration of HSPGs, deactivation of SULF-2 and reduction of gene expression of caspase-3. Targeting GPC3 is a promising therapeutic approach for HCC.