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1.
Environ Sci Pollut Res Int ; 28(14): 17482-17494, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33394435

RESUMEN

Heavy metal contamination including mercury (Hg) has become one of the most serious environmental problems facing humans and other living organisms. Here, the hepatoprotective effects of Z. spina-christi leaf extract (ZCE) against inorganic mercury salt (mercuric chloride; HgCl2)-induced hepatotoxicity model was investigated in rats. Mercury concentration, liver function markers, oxidative stress markers, inflammation, cell death indicators, and histopathology were assessed. ZCE protected against HgCl2-induced hepatotoxicity, decreased Hg concentration, lipid peroxidation, and nitric oxide, increased glutathione, superoxide dismutase, catalase, and glutathione recycling enzymes (peroxidase and reductase), and upregulated nuclear factor-erythroid 2-related factor 2 (Nrf2) gene expression in HgCl2-intoxicated rat hepatic tissue. Nrf2 downstream gene and heme oxygenase-1 were also upregulated, confirming that hepatoprotection by ZCE against HgCl2-induced liver damage involved activation of the Nrf2/antioxidant response element pathway. ZCE also decreased the expression and production of pro-inflammatory cytokines and pro-apoptotic proteins and increased anti-apoptotic protein Bcl-2. Immunohistochemical analysis of liver tissues of HgCl2-treated rats confirmed the alternations of apoptotic-related protein expression. Our data demonstrated that post-administration of ZCE attenuated HgCl2-induced liver damage by activating the Nrf2/HO-1 signaling pathway. Therefore, administering this extract may be a novel therapeutic strategy for inorganic mercury intoxication.


Asunto(s)
Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Ziziphus , Animales , Antioxidantes/metabolismo , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/metabolismo , Hígado/metabolismo , Masculino , Cloruro de Mercurio/metabolismo , Cloruro de Mercurio/toxicidad , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Extractos Vegetales/metabolismo , Extractos Vegetales/farmacología , Ratas , Ziziphus/metabolismo
2.
Artículo en Inglés | MEDLINE | ID: mdl-33280592

RESUMEN

BACKGROUND: Mercuric chloride (HgCl2) severely impairs the central nervous system when humans are exposed to it. AIMS: We investigated the neuroprotective efficiency of Ziziphus spina-christi leaf extract (ZSCLE) on HgCl2-mediated cortical deficits. METHODS: Twenty-eight rats were distributed equally into four groups: the control, ZSCLE-treated (300 mg/kg), HgCl2- treated (0.4 mg/kg), and ZSCLE+HgCl2-treated groups. Animals received their treatments for 28 days. RESULTS: Supplementation with ZSCLE after HgCl2 exposure prevented the deposition of mercury in the cortical slices. It also lowered malondialdehyde levels and nitrite and nitrate formation, elevated glutathione levels, activated its associatedantioxidant enzymes, glutathione reductase and glutathione peroxidase, and upregulated the transcription of catalase and superoxide dismutase and their activities were accordingly increased. Moreover, ZSCLE activated the expression of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 when compared with the HgCl2 group. Notably, post-treatment with ZSCLE increased the activity of acetylcholinesterase and ameliorated the histopathological changes associated with HgCl2 exposure. Furthermore, ZSCLE blocked cortical inflammation, as observed by the lowered mRNA expression and protein levels of interleukin-1 beta and tumor necrosis factor-alpha, as well as decreased mRNA expression of inducible nitric oxide synthase. In addition, ZSCLE decreased neuron loss by preventing apoptosis in the cortical tissue upon HgCl2 intoxication. CONCLUSION: Based on the obtained findings, we suggest that ZSCLE supplementation could be applied as a neuroprotective agent to decrease neuron damage following HgCl2 toxicity.

3.
IUBMB Life ; 72(10): 2121-2132, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32710811

RESUMEN

Sepsis results from a major systemic inflammatory response and can induce disorders in multiple organs. The present study evaluated the potential protective effects of oleuropein (OLE) against hyperinflammatory responses during lipopolysaccharide (LPS)-induced sepsis in mice. Sixty male Balb/c mice were randomly categorized into five groups of 12 animals each: control, intraperitoneally injected with OLE (50 mg/kg), injected with LPS (10 mg/kg, intraperitoneal), and two groups administered OLE (25 and 50 mg/kg) for 3 days prior to LPS injection. Twenty-four hours after lipopolysaccharide injection, the animals were sacrificed. Serum, liver, and kidney tissue samples were collected for biochemical analyses, histopathological examinations, and investigation of inflammation-related gene expression. OLE pretreatment significantly reduced liver damage parameters (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase) and kidney damage parameters (blood urea nitrogen, creatinine, and kidney injury molecule-1) in the septic mice. OLE pretreatment ameliorated LPS-induced liver and kidney histological changes. OLE significantly mitigated the increased levels of malondialdehyde in the liver and kidneys and reduced levels of reduced glutathione induced by LPS. LPS injection also resulted in increased expression of the proinflammatory cytokines (TNF-α, IL-1ß, and IL-6) and inflammation-related genes (Nos2, Hmgb1, Mpo, Cd46, Map2k4, and Map2k7) in the hepatic and renal tissues. OLE reduced these expressions to ameliorate the inflammatory response. Moreover, OLE pretreatment enhanced the survival rate of septic mice. In conclusion, OLE alleviated the inflammatory response to protect against LPS-induced sepsis in mice.

4.
Anticancer Agents Med Chem ; 20(9): 1061-1071, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32228431

RESUMEN

BACKGROUND: Prostate Cancer (PCa) is defined as a major health problem faced by the male population. AIM: We aimed to investigate the protective effects of Orange Peel Extract (OPE) and/or Selenium (Se) on chronic non-bacterial prostatitis in a rat model. METHODS: Fifty-six adult male Wistar albino rats were castrated; after 5 days, they were divided randomly into eight groups (n= 7). The control group received saline treatment; while 17ß-estradiol (E2) (0.25mg/kg) was injected subcutaneously in rats from Groups V, VI, VII, and VIII to induce chronic non-bacterial prostatitis. They were then treated with OPE (400mg/kg body weight; Groups II, IV, VI, and VIII) and/or sodium selenite (0.5mg/kg body weight; Groups III, IV, VII, and VIII) for 30 days. Interleukin-2 (IL2) and Prostate Cancer Antigen 3 (PCA3) mRNA expressions were determined using qPCR; Prostate-Specific Antigen (PSA) protein expression was determined immunohistochemically. Prostate tissue histology was examined by hematoxylin and eosin staining, and the levels of oxidative stress markers and antioxidant enzymes were measured. RESULTS: E2 administration significantly increased IL2 and PCA3 mRNA expressions, and PSA protein expression. It also increased the prostate wet weight and body weight, and lipid peroxidation, nitric oxide, TNF-α, and IL-1ß levels, decreased the glutathione and antioxidant enzyme levels and caused distinct histological alterations in the prostate gland. OPE and/or Se markedly improved all the studied parameters due to their antioxidant properties and anti-inflammatory effects. CONCLUSION: OPE and Se showed protective effects against 17ß-estradiol-induced chronic non-bacterial prostatitis. These results suggest that protection of chronic non-bacterial prostatitis by OPE+Se combination involves anti-oxidation and anti-inflammation. Moreover, their synergistic mechanism was mostly achieved via the regulation of oxidative stress and inflammation processes.

5.
Environ Sci Pollut Res Int ; 27(3): 2935-2944, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31838672

RESUMEN

Fucoidans (FUCs) are sulfated polysaccharides that have a wide range of bioactivities. The current study was designed to evaluate the antioxidant potential of FUC against microcystin-LR (MC-LR)-induced toxicity. Five mice groups (n = 8) were used. Group 1 received saline, Group 2 received oral FUC 100 mg/kg/day for 21 days, Group 3 received i.p. MC-LR 10 µg/kg/day for 14 days, Group 4 received MC-LR plus FUC 50 mg/kg/day, and Group 5 received MC-LR plus FUC 100 mg/kg/day. The present study showed that MC-LR administration was associated with significant increases (p < 0.01) in serum concentrations of hepatic (aspartate transferase, alanine transferase, and alkaline phosphatase), renal (urea and creatinine), and cardiac (creatine kinase and CK-MB) injury biomarkers, as well as serum lactate dehydrogenase, cholesterol, and pro-inflammatory cytokines (interleukins-1ß and 6, and tumor necrosis factor-α), compared with the control group. Further, MC-LR-intoxicated mice exhibited significantly higher (p < 0.01) hepatic, renal, and cardiac tissue levels of malondialdehyde and nitric oxide, as well as lower tissue levels of reduced glutathione and activities of glutathione peroxidase, superoxide dismutase, and catalase enzymes in comparison with control mice. Treatment by FUC significantly ameliorated all the above-mentioned alterations in a dose-dependent manner with frequent restoration of the normal ranges in the FUC 100 mg/kg/day dose group. Moreover, treatment by FUC alone at 100 mg/kg/day was not associated with significant negative alterations in the assessed biochemical parameters, highlighting its safety at this dose. In conclusion, treatment by FUC significantly ameliorated organ injury, induced by MC-LR in mouse hepatic, renal, and cardiac tissues.


Asunto(s)
Antioxidantes/farmacología , Carcinógenos/toxicidad , Microcistinas/toxicidad , Estrés Oxidativo/efectos de los fármacos , Polisacáridos/farmacología , Animales , Glutatión , Hígado , Toxinas Marinas , Ratones
6.
Environ Sci Pollut Res Int ; 27(3): 3401-3412, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31840221

RESUMEN

Mercury (Hg) is a heavy metal toxicant, causing several adverse reactions to animals and humans including reproductive dysfunction. The potential protective role of Ziziphus spina-christi leaf extract (ZSCLE) against testicular impairments associated with mercury chloride (HgCl2) exposure in rats was investigated in the current study. Four experimental groups were employed as follows (n = 7): group I served as control, group II was gavaged with ZSCLE (300 mg/kg), group III was administered with HgCl2 (0.4 mg/kg), and group IV was preadministered with ZSCLE 1 h before HgCl2. All groups were treated daily for 28 days. The exposure to HgCl2 caused a marked increase in Hg concentration in the testicular tissue, which was accompanied with a decrease in testis index. A reproductive impairment was recorded following HgCl2 exposure as verified through the decrease in levels of testosterone, luteinizing, and follicle-stimulating hormones. HgCl2 was found to enhance the development of oxidative damage in the testicular tissue as presented by the imbalance between pro-oxidants and antioxidant molecules. In addition, excessive release of tumor necrosis factor-α and interleukin-1ß was recorded in response to HgCl2 intoxication. Furthermore, a disturbance in the apoptotic proteins in favor of the pro-apoptotic proteins was also observed following HgCl2 intoxication. However, ZSCLE administration along with HgCl2 abolished significantly the molecular, biochemical, and histopathological alterations induced by HgCl2 intoxication. Our findings suggest that ZSCLE could be used to mitigate reproductive dysfunction associated with HgCl2 exposure.


Asunto(s)
Sustancias Peligrosas/toxicidad , Cloruro de Mercurio/toxicidad , Extractos Vegetales/farmacología , Sustancias Protectoras/farmacología , Ziziphus , Animales , Antioxidantes , Masculino , Mercurio , Estrés Oxidativo , Ratas , Testículo/efectos de los fármacos , Testículo/fisiología
7.
Oxid Med Cell Longev ; 2019: 5634685, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31827681

RESUMEN

Exposure to heavy metals, including mercury chloride (HgCl2), is associated with severe health problems. This study was designed to investigate HgCl2-induced nephrotoxicity and evaluate the protective role of Ziziphus spina-christi leaf extract (ZSCLE). Four randomly selected groups containing seven rats were used. For a period of 28 days, the control group was administered 0.9% saline solution; the second group was administered 300 mg/kg ZSCLE; the third group was administered 0.4 mg/kg HgCl2 dissolved in 0.9% physiological saline solution; and the fourth group was administered an oral supplement of 300 mg/kg ZSCLE one hour after HgCl2 administration. HgCl2 intoxication resulted in Hg accumulation in renal tissue; decreases in body weight, kidney index, and glutathione content and superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activities; increases in creatinine, urea, Kim-1 expression, lipid peroxidation, and nitric oxide production; suppression of the Nrf2-antioxidant response pathway; upregulation of Il1ß, Tnfα, and Nos2; and potentiation of proapoptotic activity. ZSCLE exerted beneficial effects against mercury-induced renal toxicity and significantly reversed these alterations to near normal values. These effects resulted from its chelation and antioxidant, anti-inflammatory, and antiapoptotic activities. ZSCLE may prevent or minimize the pathological changes induced by mercury in the kidney.


Asunto(s)
Apoptosis/efectos de los fármacos , Cloruro de Mercurio/toxicidad , Factor 2 Relacionado con NF-E2/metabolismo , Extractos Vegetales/farmacología , Ziziphus/química , Animales , Catalasa/metabolismo , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Creatinina/orina , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Masculino , Factor 2 Relacionado con NF-E2/genética , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/química , Hojas de la Planta/química , Hojas de la Planta/metabolismo , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Ziziphus/metabolismo
8.
Int J Mol Sci ; 20(22)2019 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-31718011

RESUMEN

The present study aimed to test the anti-inflammatory and xanthine oxidase inhibitory activities of two synthesized molecules and compare them to routinely prescribed nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac and the serum urate-lowering drug, allopurinol. The anti-inflammatory effects of the designed compounds (A and B) were evaluated in carrageenan (CAR)-induced paw edema in mice. The levels of nitric oxide and myeloperoxidase activity were measured in paw skin using biochemical methods. Additionally, prostaglandin E2 (PGE2), C-reactive protein (CRP), cyclooxygenase-2 (Cox-2), tumor necrosis factor-α (TNFα), interleukin (IL)-1ß, IL-2 and IL-10, and monocyte chemoattractant protein-1 (MCP1) were assessed by enzyme-linked immunosorbent assay (ELISA). The expression of inflammation-related genes was confirmed by real-time qPCR. The expression of inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB) were estimated using immunohistochemistry, and xanthine oxidase inhibitory activity was evaluated using an in vitro assay. The results revealed that compounds A and B decreased inflammation, as was observed by a reduction in the elevation of all the tested markers. In addition, the tested compounds markedly decreased paw swelling, mobilization of inflammatory cells, iNOS-, and NF-κB-immunoreactive cells in a mouse model of paw edema. Interestingly, both compounds were potent xanthine oxidase inhibitors as well as Cox inhibitors with higher activity in favor of compound B providing potential dual acting series of anti-hyperuricemic and anti-inflammatory therapeutic agents.


Asunto(s)
Antiinflamatorios/farmacología , Edema/tratamiento farmacológico , Supresores de la Gota/farmacología , Animales , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Proteína C-Reactiva/análisis , Células Cultivadas , Quimiocina CCL2/metabolismo , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Supresores de la Gota/química , Supresores de la Gota/uso terapéutico , Interleucinas/metabolismo , Masculino , Ratones , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Peroxidasa/metabolismo , Piel/efectos de los fármacos , Piel/metabolismo , Piel/patología , Factor de Necrosis Tumoral alfa/metabolismo , Xantina Oxidasa/antagonistas & inhibidores
9.
PLoS One ; 14(6): e0216737, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31194753

RESUMEN

Gastric ulcer is sores that form in the stomach mucosal layer because of erosion caused by high acid secretion and excessive use of non-steroidal anti-inflammatory drugs. Prodigiosins (PdGs) are red-pigmented secondary metabolites produced by bacteria, including actinomycetes. Butylcycloheptylprodigiosin (1) and undecylprodigiosin (2) were identified and isolated from a crude extract of the actinomycete RA2 isolated from the Red Sea Sponge Spheciospongia mastoidea. Chemical structure of 1 and 2 was determined by NMR and mass spectroscopy. Although their antioxidant and anti-inflammatory properties are known, their effect on gastric lesion is unknown. Therefore, this study aimed to investigate gastroprotective effects of PdGs against HCl/ethanol-induced gastric lesion in rats. Oral pretreatment with PdGs (100, 200, and 300 mg/kg) attenuated severity of HCl/ethanol-induced gastric mucosal injury, as evidenced by decreases in gastric lesion index scores, ulceration area, histopathologic abnormality, and neutrophil infiltration. These effects were comparable to those of omeprazole, a standard anti-gastric ulcer agent. HCl/ethanol-induced gastric erosions was associated with tremendous increases in lipid peroxidation, nitric oxide, and pro-inflammatory cytokines and mediators (myeloperoxidase, interleukin-1ß, tumor necrosis factor-α, and cyclooxygenase-2), and with significant decreases in enzymatic and non-enzymatic antioxidant activities. However, PdGs ameliorated gastric inflammation and oxidative stress by downregulating nuclear factor kappa B and inducible nitric oxide synthase expression and upregulating heme oxygenase-1 expression. PdGs prevented gastric mucosal apoptosis by downregulating Bax and caspase-3 expression and upregulating Bcl-2 expression, thereby increasing prostaglandin E2 production. Our results suggested that PdGs exerted gastroprotective effects by decreasing the levels of inflammatory mediators, apoptotic markers, and antioxidants.


Asunto(s)
Antiinflamatorios/farmacología , Antioxidantes/farmacología , Etanol/efectos adversos , Mucosa Gástrica/patología , Ácido Clorhídrico/efectos adversos , Poríferos/química , Prodigiosina/farmacología , Animales , Apoptosis/efectos de los fármacos , Citoprotección/efectos de los fármacos , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar
10.
Sci Rep ; 9(1): 5825, 2019 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-30967588

RESUMEN

Cadmium exposure induces nephrotoxicity by mediating oxidative stress, inflammation, and apoptosis. The purpose of this study was to examine the protective effect of royal jelly on Cd-induced nephrotoxicity. Adult male mice were distributed randomly into 4 clusters: untreated, royal jelly-treated (85 mg/kg, oral), CdCl2-treated (6.5 mg/kg, intraperitoneal), and pretreated with royal jelly (85 mg/kg) 2 h before CdCl2 injection (6.5 mg/kg, intraperitoneal) for seven consecutive days. Cd concentration in the renal tissue and absolute kidney weight of the Cd-treated mice were significantly higher than those of control group. The levels of kidney function markers, kidney injury molecules-1 (KIM-1), metallothionein, lipid peroxidation, nitric oxide, tumor necrosis factor-α, interleukin-1ß, and the apoptosis regulators Bax and caspases-3 also increased significantly in the renal tissue of Cd-treated mice, whereas the levels of glutathione, antioxidant enzyme activities, and the apoptosis inhibitor Bcl-2 were significantly reduced in the renal tissue of Cd-treated group. Histopathological studies showed vacuolation and congested glomeruli in the kidney tissue of Cd-treated mice. However, all aforementioned Cd-induced changes were attenuated by pretreatment with royal jelly. We therefore concluded that royal jelly attenuated Cd-induced nephrotoxicity and it is suggested that this nephroprotective effect could be linked to its ability to promote the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant responsive element (ARE) pathway.


Asunto(s)
Lesión Renal Aguda/prevención & control , Intoxicación por Cadmio/prevención & control , Cadmio/toxicidad , Ácidos Grasos/farmacología , Hormonas de Insectos/farmacología , Sustancias Protectoras/farmacología , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Intoxicación por Cadmio/tratamiento farmacológico , Inflamación/inducido químicamente , Riñón/patología , Masculino , Ratones , Estrés Oxidativo/efectos de los fármacos
11.
Environ Sci Pollut Res Int ; 26(15): 15248-15254, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30929167

RESUMEN

Nephrotoxicity is a common adverse effect of treatment with cisplatin (CDDP). This study was performed to evaluate the antioxidant and nephroprotective efficacy of ceftriaxone (CTX) and vitamin E (Vit.E), alone and in combination against CDDP-induced acute renal injury. Fifty-six male albino rats were equally divided into seven groups, receiving (I) normal saline, (II) CTX (100 mg/kg, intraperitoneal [i.p] injection), (III) Vit.E (100 mg/kg orally), (IV) CDDP (5 mg/kg i.p injection), (V) CDDP plus CTX, (VI) CDDP plus Vit.E, and (VII) CDDP plus CTX in combination with Vit.E. All treatments were administered daily for 10 days except CDDP, which was given as a single dose at the sixth day of the study. Compared to normal control rats, CDDP-injected rats showed significantly (p < 0.05) higher serum levels of renal injury biomarkers (uric acid, urea, and creatinine) and tumor necrosis factor-α (TNF-α), as well as increased renal tissue concentrations of malondialdehyde, nitric oxide, and TNF-α. Moreover, CDDP administration was associated with significantly lower (p < 0.05) renal tissue levels of reduced glutathione and activities of endogenous antioxidant enzymes (glutathione peroxidase, superoxide dismutase, and catalase) and total antioxidant capacity. All these alterations were significantly ameliorated in CDDP-injected rats, receiving CTX and/or Vit.E, compared to rats receiving CDDP alone. Interestingly, the antioxidant and anti-inflammatory effects were more marked in the CTX-Vit.E combination group, compared to groups receiving either drug alone. In conclusion, CTX and Vit.E (especially in combination) could counteract the nephrotoxic effect of CDDP, probably through their antioxidant activities.


Asunto(s)
Antioxidantes/farmacología , Catalasa/química , Ceftriaxona/farmacología , Cisplatino/toxicidad , Glutatión Peroxidasa/química , Glutatión/farmacología , Riñón/efectos de los fármacos , Malondialdehído/farmacología , Óxido Nítrico/farmacología , Superóxido Dismutasa/química , Urea/sangre , Vitamina E/farmacología , Animales , Creatinina/sangre , Glutatión/química , Inyecciones Intraperitoneales , Masculino , Malondialdehído/química , Ratas
12.
Food Chem Toxicol ; 127: 110-119, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30853555

RESUMEN

Candelariella vitellina is common green-yellow lichen found on barks, wood, and rocks in Japanese forests. To investigate the mechanism of its anticancer potential, C. vitellina (80% MeOH/H2O) extract was prepared. High-performance liquid chromatography-high-resolution electrospray ionization mass spectrometry analysis revealed seven new compounds and 11 natural compounds of terpenes and polyketides. In vitro cytotoxicity analysis of Caco-2 cells exhibited an IC50 of 125 ±â€¯4.1 µg/mL. No significant cytotoxicity was observed in vitro in normal human peripheral lymphocytes. Both the IC25 and IC50 were determined to explore the potent anticancer potential in this study. C. vitellina exhibited a mitochondrial P53-independent apoptotic effect with negative P53 expression and an elevated BAX/BCL2 ratio as well as upregulated CASP3 mRNA expression. Similarly, in vivo analysis showed the same pattern of anticancer potential but was dependent on the P53 expression. Furthermore, C. vitellina induced antioxidative conditions in vitro and in vivo. The decreased invasion of tumor cells in vivo and increased apoptotic features in vitro and in vivo suggest the moderate to strong apoptotic anticancer potential of C. vitellina. However, further studies are needed to determine the extent and mechanism of action on different cell lines to support the anticancer properties of this lichen.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Líquenes/química , Extractos Vegetales/farmacología , Animales , Antineoplásicos Fitogénicos/aislamiento & purificación , Antioxidantes/farmacología , Apoptosis/genética , Células CACO-2 , Carcinoma de Ehrlich/patología , Supervivencia Celular/efectos de los fármacos , Cromatografía Liquida , Femenino , Humanos , Técnicas In Vitro , Ratones , Estrés Oxidativo , Policétidos/aislamiento & purificación , Policétidos/farmacología , ARN Mensajero/genética , Espectrometría de Masa por Ionización de Electrospray , Terpenos/aislamiento & purificación , Terpenos/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
13.
Onco Targets Ther ; 12: 21-30, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30588027

RESUMEN

Introduction: The communication between a substance and a cell may depend on whether the cell is normal or pathological. The disease cells and drug interaction may occasionally overcome beneficial action of the drug; subsequently, it is important to investigate the effect of the drug in both the normal and target cells. This study aimed to evaluate the methotrexate (MTX) antiproliferative effect and explore the mechanistic approach to investigate the cell death index in SKOV-3 ovarian cells during treatment with MTX. Methods: In vitro studies of SKOV-3 cells were examined by tetrazolium assay after exposure to various concentrations of MTX. Moreover, reactive oxygen species (ROS) generation, mitochondrial membrane potential, DNA damage, and AO/EtBr staining morphological analysis of necrotic/apoptotic cells were detected; cellular impairment in mitochondria and DNA was confirmed by JC-1 mitotracker/DAPI, respectively, and cell death pathway markers; bax/bcl-2 were analyzed. Results: A dose-dependent antiproliferative effect of MTX treatment was observed in SKOV-3 cells; the prominent inhibitory concentration was 40 µM of MTX (P<0.01). The growth inhibition rates of the cancer cells reached 24.07% in MTX. The MTX showed increase in ROS generation and mitochondrial depolarization, and DNA integrity cells collectively advocated the apoptotic cell death at higher concentration. In addition, the results of reverse transcription polymerase chain reaction also supported the apoptosis by upregulating the bax and downregulating the bcl-2 (P<0.01). Thus the MTX moderately provokes apoptosis. Conclusion: Our findings suggest that MTX acts on SKOV-3 cancer cells by increasing intracellular ROS levels, leading to DNA damage and altering the MMP along with apoptotic gene upregulation. This mechanism may provide new therapeutic targets to improve tumor treatment.

14.
Mol Biol Rep ; 46(1): 119-131, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30414103

RESUMEN

This study aimed to evaluate the potential neuroprotective effect of royal jelly (RJ) against Cd-induced neuronal damage. Twenty-eight adult mice were placed equally into four groups. The control group received intraperitoneal (IP) injections of normal saline; the cadmium chloride (CdCl2) group was IP-injected 6.5 mg/kg (mg per kg of bodyweight) CdCl2; the RJ group was gavaged 85 mg/kg RJ; and the RJ + CdCl2 group was orally administered 85 mg/kg RJ 2 h before receiving IP-injections of 6.5 mg/kg CdCl2. All groups were treated for seven consecutive days and the mice were decapitated 24 h after the final dose. Cd accumulation was recorded in the cortical homogenates, accompanied by elevated levels of lipid peroxidation, nitric oxide, tumor necrosis factor-α, interleukin-1ß, and the pro-apoptotic mRNA Bax and caspase-3. Meanwhile, significantly decreased levels of detoxifying antioxidant enzymes including GSH-Px, GSH-R, SOD, and CAT, anti-apoptotic mRNA Bcl-2, and monoamines such as norepinephrine, dopamine, and serotonin were also observed, along with reduced gene expression of Nrf2-dependent antioxidants. Interestingly, in mice pretreated with RJ, the assessed parameters remained near normal levels. Our data provide evidence that RJ treatment has the potential to protect cortical neurons in Cd-intoxicated mice via its antioxidant, anti-inflammatory, anti-apoptotic, and neuromodulatory activity.


Asunto(s)
Ácidos Grasos/farmacología , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Encéfalo/efectos de los fármacos , Cadmio/efectos adversos , Cadmio/farmacología , Cloruro de Cadmio/metabolismo , Ácidos Grasos/metabolismo , Interleucina-1beta/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones , Neuronas/metabolismo , Fármacos Neuroprotectores/metabolismo , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología , Factor de Necrosis Tumoral alfa/efectos de los fármacos
15.
Anticancer Agents Med Chem ; 19(3): 356-364, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30451117

RESUMEN

BACKGROUND: Berberine and cinnamic acid are natural compounds that exhibit potent anticancer activities through distinct molecular mechanisms. OBJECTIVE: In the present study, we aimed to investigate the proapoptotic potential of cinnamic acid and berberine in cancer cells by examining their effect on the expression of proapoptotic and antiapoptotic genes. Moreover, the effects of berberine and cinnamic acid on the antitumor activity of cisplatin were investigated in Ehrlich solid tumor-bearing mice. METHODS: For the study, 90 male mice were inoculated intramuscularly with Ehrlich ascites tumor cells (2.5 × 106/mouse), and then on day 4, mice were randomly divided into six experimental groups (group 1-untreated Ehrlich solid tumor (EST), group 2-EST treated CDDP, group 3-EST treated CA, group 4-EST treated BER, group 5-EST treated CA + CDDP, and group 6-EST treated BER + CDDP). RESULTS: The results showed that berberine and cinnamic acid significantly decreased tumor growth and tumor volume (-74.8 and -75.5%, respectively) both as single agents and in combination with cisplatin. Moreover, both berberine and cinnamic acid increased the ratio of tumor growth inhibition (-91.5 and -92.6%, respectively), mean survival time (61.5 and 26 days, respectively), and percentage increase in lifespan (559 and 263%, respectively) of the treated mice. Our results also showed that both berberine and cinnamic acid-induced apoptosis by increasing the Bax/Bcl-2 ratio (74.1 and 45.1, respectively) and caspase-3 expression (14.3- and 11.6-fold increase, respectively). Additionally, berberine and cinnamic acid decreased oxidative stress markers, as shown by the decrease in lipid peroxidation and nitric oxide levels and an increase in reduced glutathione level. CONCLUSION: These results suggest that berberine and cinnamic acid have potential as antitumor and antioxidant agents derived from natural sources, which could be used alone or in combination with regular chemotherapeutic agents, such as cisplatin. These effects could be attributed to the proapoptotic activity of berberine and cinnamic acid.


Asunto(s)
Antineoplásicos/farmacología , Berberina/farmacología , Carcinoma de Ehrlich/tratamiento farmacológico , Cinamatos/farmacología , Animales , Antineoplásicos/química , Berberina/química , Biomarcadores de Tumor/análisis , Carcinoma de Ehrlich/patología , Proliferación Celular/efectos de los fármacos , Cinamatos/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Masculino , Malondialdehído/análisis , Ratones , Estructura Molecular , Estrés Oxidativo/efectos de los fármacos , Relación Estructura-Actividad
16.
Int J Mol Sci ; 19(12)2018 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-30544760

RESUMEN

The current study examined the efficacy of royal jelly (RJ) against cadmium chloride (CdCl2)-induced testicular dysfunction. A total of 28 Swiss male mice were allocated into four groups (n = 7), and are listed as follows: (1) the control group, who was intraperitoneally injected with physiological saline (0.9% NaCl) for 7 days; (2) the RJ group, who was orally supplemented with RJ (85 mg/kg daily equivalent to 250 mg crude RJ) for 7 days; (3) the CdCl2 group, who was intraperitoneally injected with 6.5 mg/kg for 7 days; and (4) the fourth group, who was supplemented with RJ 1 h before CdCl2 injection for 7 days. Cd-intoxicated mice exhibited a decrease in serum testosterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH) levels. A disturbance in the redox status in the testicular tissue was recorded, as presented by the increase in lipid peroxidation and nitrate/nitrite levels and glutathione (GSH) depletion. Moreover, the activities of glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), and nuclear factor (erythroid-derived 2)-like-2 factor (Nrf2) and their gene expression were inhibited. In addition, interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) levels were elevated. Furthermore, Cd triggered an apoptotic cascade via upregulation of caspase-3 and Bax and downregulation of Bcl-2. Histopathological examination showed degenerative changes in spermatogenic cells, detachment of the spermatogenic epithelium from the basement membrane, and vacuolated seminiferous tubules. Decreased cell proliferation was reflected by a decrease in proliferating cell nuclear antigen (PCNA) expression. Interestingly, RJ supplementation markedly minimized the biochemical and molecular histopathological changes in testes tissue in response to Cd exposure. The beneficial effects of RJ could be attributed to its antioxidative properties.


Asunto(s)
Cadmio/toxicidad , Ácidos Grasos/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Testículo/metabolismo , Testículo/patología , Animales , Apoptosis/efectos de los fármacos , Ácidos Grasos/administración & dosificación , Hormona Folículo Estimulante/sangre , Glutatión/metabolismo , Inflamación/patología , Peroxidación de Lípido/efectos de los fármacos , Hormona Luteinizante/sangre , Masculino , Ratones , Factor 2 Relacionado con NF-E2/genética , Nitratos/metabolismo , Nitritos/metabolismo , Tamaño de los Órganos/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Testículo/efectos de los fármacos , Testosterona/sangre
17.
Dose Response ; 16(4): 1559325818807382, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30479585

RESUMEN

Metal nanoparticles are widely used in industry, agriculture, textiles, drugs, and so on. The adverse effect of green platinum nanoparticles on human embryonic kidney (HEK293) cells is not well established. In the current study, green platinum nanoparticles were synthesized using leaf extract of Azadirachta indica L. Green platinum nanoparticles were characterized by dynamic light scattering and transmission electron microscope. The cytotoxicity of green platinum nanoparticle was observed in HEK293 cells by applying 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) and Neutral red uptake (NRU) assays. Cell viability of the cells was decreased in a concentration and duration-dependent manner. Generation of reactive oxygen species (ROS) in HEK293 cells due to green platinum nanoparticles was examined using fluorescent dye 2,7-dichlorofluorescein diacetate (DCFDA), and ROS was increased according to exposure pattern. The cytotoxicity of HEK293 cells was correlated with increased caspase 3, depolarization of mitochondrial membrane potential, and DNA fragmentation. The abovementioned finding confirmed that mitochondria play an important role in genotoxicity and cytotoxicity induced by nanoparticles in HEK293 cells. Further, we determined other oxidative stress biomarkers, lipid peroxide (LPO) and glutathione (GSH); LPO was increased and GSH was decreased in HEK293 cells. It is also important to indicate that HEK293 cells appear to be more susceptible to green platinum nanoparticles exposure after 24 hours. This result provides a dose- and time-dependent apoptosis and genotoxicity of green nanoparticles on HEK293 cells.

18.
PLoS One ; 13(10): e0204923, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30273397

RESUMEN

Schistosomiasis is a widespread parasitic infection that affects humans, as well as wild and domestic animals. It ranks second after malaria, with a significant health and socio-economic impact in the developing countries. The objective of this study was to assess the anti-schistosomal impact of Ziziphus spina-christi leaf extract (ZLE) on Schistosoma mansoni-induced liver fibrosis in CD-1 Swiss male albino mice. S. mansoni infection was achieved by dipping of mouse tails in schistosomal cercariae. ZLE treatment was initiated at 46 days post-infection by administering a dose of the extract on a daily basis for 10 consecutive days. S. mansoni infection resulted in liver granuloma and fibrosis, with a drastic elevation in liver function factors, nitric oxide, and lipid peroxidation, which were associated with a reduction in glutathione content and substantial inhibition of antioxidant enzyme activities compared to those of the control. Induction of hepatic granuloma, oxidative stress, and fibrosis in the liver was controlled by ZLE administration, which also produced inhibition of matrix metalloproteinase-9, alpha-smooth muscle actin, transforming growth factor-ß, and tissue inhibitors of metalloproteinases expressions. In addition, the S. mansoni-infected group exhibited an increase in Bax and caspase-3 levels and a decrease in Bcl-2 level. However, treatment with ZLE mainly mitigated apoptosis in the liver. Thus, the findings of this study revealed that Ziziphus spina-christi had anti-apoptotic, anti-fibrotic, antioxidant, and protective effects on S. mansoni-induced liver wounds. The benefits of Ziziphus spina-christi extract on S. mansoni were partly partially mediated by enhancing anti-fibrinogenic and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways.


Asunto(s)
Cirrosis Hepática/parasitología , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/administración & dosificación , Esquistosomiasis mansoni/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Ziziphus/química , Animales , Modelos Animales de Enfermedad , Regulación hacia Abajo , Esquema de Medicación , Fibrinógeno/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Cirrosis Hepática/fisiopatología , Pruebas de Función Hepática , Masculino , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , Extractos Vegetales/farmacología , Hojas de la Planta/química , Esquistosomiasis mansoni/metabolismo , Esquistosomiasis mansoni/fisiopatología
19.
Biosci Rep ; 38(6)2018 12 21.
Artículo en Inglés | MEDLINE | ID: mdl-30291211

RESUMEN

Cadmium (Cd) is a common environmental toxicant that has harmful effects on plants, animals, and humans. The present study evaluated the protective effects of Fragaria ananassa methanolic extract (SME) on cadmium chloride (CdCl2)-induced neuronal toxicity in rats. Male albino rats were intraperitoneally (i.p) injected with CdCl2 (6.5 mg/kg) for 5 days with or without the SME (250 mg/kg). We measured the levels of Cd, lipid peroxidation (LPO), nitric oxide, glutathione (GSH), and oxidative enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase, and glutathione reductase (GR) in the whole brain homogenate. Compared with the control group, the Cd-intoxicated group showed a marked increase in the brain levels of Cd, LPO, and nitric oxide and a decrease in the levels of GSH and all tested antioxidant enzymes. Compared with Cd-intoxicated rats, the rats pretreated with SME showed restoration of oxidative balance in the brain tissue. While the expression of brain SOD2, CAT, glutathione peroxidase 1, and GR was down-regulated in the Cd-treated group, the expression of these enzymes was up-regulated in rats pretreated with SME. In addition, administration of SME before CdCl2 increased the Bcl-2 expression, but significantly decreased the expression of Bax. Immunohistochemical analysis showed that compared with Cd-intoxicated rats, rats pretreated with SME showed a decrease in the protein expression of tumor necrosis factor α (TNF-α). Our findings indicate that SME protects the brain tissue from Cd-induced neuronal toxicity by improving the antioxidant system and increasing antiapoptotic and anti-inflammatory activities.


Asunto(s)
Cloruro de Cadmio/toxicidad , Fragaria/química , Neuronas/efectos de los fármacos , Extractos Vegetales/administración & dosificación , Animales , Antioxidantes/administración & dosificación , Antioxidantes/química , Apoptosis/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Peroxidación de Lípido/efectos de los fármacos , Neuronas/patología , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/química , Sustancias Protectoras/administración & dosificación , Sustancias Protectoras/química , Ratas , Factor de Necrosis Tumoral alfa/genética
20.
Int J Nanomedicine ; 13: 5685-5699, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30288041

RESUMEN

Introduction: Graphene oxide nanoparticles have been widely used in industry and biomedical fields due to their unique physicochemical properties. However, comparative cytotoxicity of silver-doped reduced graphene oxide (rGO-Ag) nanoparticles on normal and cancerous liver cells has not been well studied yet. Materials and methods: This study aimed at determining the toxic potential of rGO-Ag nanocomposite on human liver normal (CHANG) and cancer (HepG2) cells. The rGO-Ag nanocomposite was characterized by using different advanced instruments, namely, dynamic light scattering, scanning electron microscope, and transmission electron microscope. Results: The rGO-Ag nanocomposite reduced cell viability and impaired cell membrane integrity of CHANG and HepG2 cells in a dose-dependent manner. Additionally, it induced reactive oxygen species generation and reduced mitochondrial membrane potential in both cells in a dose-dependent manner. Moreover, the activity of oxidative enzymes such as lipid peroxide, superoxide dismutase, and catalase were increased and glutathione was reduced in both cells exposed to rGO-Ag nanocomposite. Pretreatment with N-acetylcysteine inhibited cytotoxicity and reactive oxygen species generation in CHANG and HepG2 cells exposed to rGO-Ag nanocomposite (50 µg/mL). DNA damage was determined by Comet assay and maximum DNA damage occurred at rGO-Ag nanocomposite (25 µg/mL) for 24 h. It is also valuable to inform that HepG2 cells appear to be slightly more susceptible to rGO-Ag nanocomposite exposure than CHANG cells. Conclusion: This result provides a basic comparative toxic effect of rGO-Ag nanocomposite on hepatic normal and cancerous liver cells.


Asunto(s)
Apoptosis , Grafito/química , Neoplasias Hepáticas/patología , Hígado/patología , Nanocompuestos/química , Plata/química , Acetilcisteína/farmacología , Apoptosis/efectos de los fármacos , Catalasa/metabolismo , Forma de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Daño del ADN , Glutatión/metabolismo , Células Hep G2 , Humanos , Peróxidos Lipídicos/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Nanopartículas del Metal/química , Nanocompuestos/ultraestructura , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismo
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