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1.
Environ Sci Pollut Res Int ; 28(27): 35488-35527, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34024001

RESUMO

The wide use of phthalates, as phthalates are used in the manufacturing of not only plastics but also many others goods, has become a main concern in the current century because of their potency to induce deleterious effects on organism health. The toxic effects of phthalates such as reproductive toxicity, cardiotoxicity, hepatotoxicity, nephrotoxicity, teratogenicity, and tumor development have been widely indicated by previous experimental studies. Some of the important mechanisms of toxicity by phthalates are the induction and promotion of inflammation, oxidative stress, and apoptosis. Awareness of the involved molecular pathways of these mechanisms will permit the detection of exact molecular targets of phthalates to protect or treat their toxicity. Up to now, various transcription factors and signaling pathways have been associated with phthalate-induced toxicity which by influencing on nuclear surface and the expression of different genes can alter cell hemostasis. In different studies, the role of nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor-κB (NF-κB), and phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathways in processes of oxidative stress, inflammation, apoptosis, and cancer has been shown following exposure to phthalates. In the present review, we aim to survey experimental studies (in vitro and in vivo) in order to show firstly the most involved receptors and also the importance and the role of the mentioned signaling pathways in phthalate-induced toxicity, and with considering this point, the future studies can focus on these molecular targets as a strategic method to reduce environmental chemicals-induced toxicity especially phthalates toxic effects.


Assuntos
NF-kappa B , Ácidos Ftálicos , Fator 2 Relacionado a NF-E2/genética , Fosfatidilinositol 3-Quinases , Ácidos Ftálicos/toxicidade , Proteínas Proto-Oncogênicas c-akt/genética
2.
J Biochem Mol Toxicol ; 35(8): e22821, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34036678

RESUMO

The preservation of the redox homeostasis is critical for cell survival and functionality. Redox imbalance is an essential inducer of several pathological states. CD4+ /helper T cells are highly dependent on the redox state of their surrounding milieu. The potential of the aryl hydrocarbon receptor (AhR) engagement in controlling CD4+ T-cell fate during redox alteration is still challenging. C57BL/6 mice were treated with AhR agonist 6-formylindolo[3,2-b]carbazole (FICZ), AhR antagonist CH223191, an inhibitor of glutathione biosynthesis buthionine sulfoximine (BSO), and the antioxidant N-acetylcysteine (NAC) alone or in combination. Six days later, splenocytes were evaluated for the expression of the redox-related genes and the possible changes in T-cell subsets. FICZ like BSO significantly elevated the expression of HMOX1, GCLC, and GCLM genes but it failed to increase the expression of the Nrf2 gene. Moreover, FICZ + BSO increased while FICZ + CH223191 or NAC decreased the expression of these genes. FICZ also significantly increased Th1 cell numbers but decreased Tregs in a dose-dependent manner. Furthermore, a high dose of FICZ + CH223191 + NAC significantly enhanced Th1, Th17, and Treg cells but its low dose in such a situation increased Th2 and Th17 while decreased Treg cells. AhR engagement during redox alteration can determine the fate of CD4 + T cells, so, AhR agonists or antagonists might be useful in assessing immune responses. However, these results need further verifications in vitro and in animal models of various diseases.


Assuntos
Receptores de Hidrocarboneto Arílico , Linfócitos T Auxiliares-Indutores/metabolismo , Acetilcisteína/farmacologia , Animais , Compostos Azo/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glutamato-Cisteína Ligase/biossíntese , Heme Oxigenase-1/biossíntese , Proteínas de Membrana/biossíntese , Camundongos , Fator 2 Relacionado a NF-E2/biossíntese , Oxirredução/efeitos dos fármacos , Pirazóis/farmacologia , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/metabolismo
3.
Toxicol Rep ; 8: 331-336, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33659189

RESUMO

Recent advances in the use of magnetite nanoparticles for biomedical applications have led to special attention to these nanoparticles. The unique properties of magnetite nanoparticles such as superparamagnetism, low toxicity, and the ability to bond with biological molecules, are suitable for drug delivery, diagnostic methods and therapeutic approaches. The aim of this study was to synthesize magnetite nanoparticles with different biocompatible coatings and investigate their cytotoxicity. Magnetite nanoparticles were synthesized by co-precipitation method and the cytotoxicity of these nanoparticles was investigated with Hepatoma G2 cell using the MTT assay. Treated cells, did not showed any evident cell cycle arrest. The Fourier Transmission Infrared (FTIR) spectroscopy, X- ray powder Diffraction (XRD), Transmission Electron Microscopy (TEM) were evaluated. The results of XRD showed the coated magnetite nanoparticles were 10-12 nm and this size also achieved with TEM images. Synthesized magnetite nanoparticles with SiO2 and oleic acid coatings had lower cytotoxicity than other coatings.

4.
Sci Rep ; 11(1): 2065, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33483573

RESUMO

In this study, the effect of the plasmon hybridization mechanism on the performance and refractive index (RI) sensitivity of nanoshell, nanocage and nanoframe structures is investigated using the finite-difference time-domain simulation. To create nanocage structure, we textured the cubic nanoshell surfaces and examined the impact of its key parameters (such as array of cavities, size of cavities and wall thickness) on the nanocage's RI-sensitivity. Synthesis of the designed nanocages is a challenging process in practice, but here the goal is to understand the physics lied behind it and try to answer the question "Why nanoframes are more sensitive than nanocages?". Our obtained results show that the RI-sensitivity of nanocage structures increases continuously by decreasing the array of cavities. Transforming the nanocage to the nanoframe structure by reducing the array of cavities to a single cavity significantly increases the RI-sensitivity of the nanostructure. This phenomenon can be related to the simultaneous presence of symmetric and asymmetric plasmon oscillations in the nanocage structure and low restoring force of nanoframe compared to nanocage. As the optimized case shows, the proposed single nanoframe with aspect ratio (wall length/wall thickness) of 12.5 shows RI-sensitivity of 1460 nm/RIU, the sensitivity of which is ~ 5.5 times more than its solid counterpart.

5.
Int J Toxicol ; 40(2): 153-160, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33438493

RESUMO

Melanin is a group of natural pigments that determines the human skin color and provides fundamental protection against the harmful impacts of physical and chemical stimuli. The aim of this study was to establish the regulatory role of aryl hydrocarbon receptor (AhR) in α-melanocyte-stimulating hormone (α-MSH) induced melanogenesis. In the present study, following knockdown of AhR, murine B16F10 cells were treated with α-MSH (200 nM) and tyrosinase activities, cellular melanin content, mRNA levels of several important genes involved in melanogenesis including AhR, CTNNB1, TYR2, and microphthalmia-associated transcription factor (MITF) were measured as endpoints. Exposure to α-MSH led to elevated expression of AhR, CTNNB1, MITF, and TYR in accordance with increased tyrosinase enzyme activity as well as a significant rise in the total melanin content. Our results suggest that AhR plays a regulatory role in α-MSH-stimulated melanogenesis.

6.
Biomed Res Int ; 2020: 2624734, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33381544

RESUMO

Mg2+ is an important cation in our body. It is an essential cofactor for many enzymes. Despite many works, nothing is known about the protective effects of MgSO4 against hypoxia-induced lethality and oxidative damage in brain mitochondria. In this study, antihypoxic and antioxidative activities of MgSO4 were evaluated by three experimental models of induced hypoxia (asphyctic, haemic, and circulatory) in mice. Mitochondria protective effects of MgSO4 were evaluated in mouse brain after induction of different models of hypoxia. Antihypoxic activity was especially pronounced in asphyctic hypoxia, where MgSO4 at dose 600 mg/kg showed the same activity as phenytoin, which used as a positive control (P < 0.001). In the haemic model, MgSO4 at all used doses significantly prolonged latency of death. In circulatory hypoxia, MgSO4 (600 mg/kg) doubles the survival time. MgSO4 significantly decreased lipid peroxidation and protein carbonyl and improved mitochondrial function and glutathione content in brain mitochondria compared to the control groups. The results obtained in this study showed that MgSO4 administration has protective effects against lethality induced by different models of hypoxia and improves brain mitochondria oxidative damage.


Assuntos
Encéfalo/efeitos dos fármacos , Hipóxia/tratamento farmacológico , Sulfato de Magnésio/farmacologia , Estresse Oxidativo , Animais , Antioxidantes/farmacologia , Asfixia/fisiopatologia , Encéfalo/metabolismo , Lesões Encefálicas , Modelos Animais de Doenças , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios/metabolismo , Fenitoína/análise , Resultado do Tratamento
7.
Int J Nanomedicine ; 15: 10085-10098, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33363368

RESUMO

Purpose: Hepatic encephalopathy (HE) is a critical situation in which liver failure affects brain function. HE could result in a state of coma and death. The liver is the main organ for ammonium ion (NH4 +) metabolism. Hence, acute and/or chronic liver failure could lead to hyperammonemia. NH4 + is the most suspected neurotoxic agent in HE. Thus, finding new therapeutic options to decrease plasma and brain NH4 + levels has a significant clinical value. Mesoporous silica (MS) particles have revolutionized many aspects of pharmaceutical sciences, including drug delivery systems. Moreover, recently, MS has been applied as agents for the detoxification of chemicals (eg, drugs and poisons). Methods: First, MS particles containing amine groups (MS-NH2) were synthesized in co-condensation processes. Then, the structure was modified by succinic anhydride to have MS-SA. The MS-SA was characterized (FT-IR, XRD, X-ray photoelectron spectroscopy (XPS), DLS-Zeta FESEM-EDX, and HRTEM). Then, the potential of MS-NH2 and MS-SA particles in adsorption of NH4 + was investigated in vitro and in vivo. MS-NH2 and MS-SA were incubated with increasing concentrations (0.1-10 mM) of NH4 +, and the scavenging capacity of the investigated particles was evaluated. On the other hand, different doses (1 and 5 mg/kg per day) of nanoparticles were administered to a hyperammonemia animal model. Results: It was figured out that both MS-NH2 and MS-SA significantly scavenged NH4 + in the in vitro model. However, the NH4 + scavenging capability of MS-SA was more significant. Administration of MS-NH2 and MS-SA also considerably decreased the level of ammonium in plasma and brain and improved cognitive and locomotor activity in hyperammonemic animals. The effects of MS-SA were more significant than MS-NH2 in the HE animal model. Conclusion: Collectively, our data suggest that MS particles, especially succinic acid-functionalized MS, could act as special ancillary treatment in HE as a critical clinical complication.


Assuntos
Amônia/isolamento & purificação , Encefalopatia Hepática/terapia , Dióxido de Silício/química , Ácido Succínico/química , Adsorção , Animais , Biomarcadores/sangue , Encéfalo/metabolismo , Modelos Animais de Doenças , Encefalopatia Hepática/sangue , Encefalopatia Hepática/fisiopatologia , Íons , Fígado/patologia , Masculino , Atividade Motora , Nanopartículas/química , Tamanho da Partícula , Espectroscopia Fotoeletrônica , Porosidade , Ratos Sprague-Dawley , Espectrometria por Raios X , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática , Difração de Raios X
8.
Clin Exp Hepatol ; 6(3): 207-219, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33145427

RESUMO

Cirrhosis-induced heart injury and cardiomyopathy is a serious consequence of this disease. It has been shown that bile duct ligated (BDL) animals could serve as an appropriate experimental model to investigate heart tissue injury in cirrhosis. The accumulation of cytotoxic chemicals (e.g., bile acids) could also adversely affect the heart tissue. Oxidative stress and mitochondrial impairment are the most prominent mechanisms of bile acid cytotoxicity. Taurine (Tau) is the most abundant non-protein amino acid in the human body. The cardioprotective effects of this amino acid have repeatedly been investigated. In the current study, it was examined whether mitochondrial dysfunction and oxidative stress are involved in the pathogenesis of cirrhosis-induced heart injury. Rats underwent BDL surgery. BDL animals received Tau (50, 100, and 500 mg/kg, i.p.) for 42 consecutive days. A significant increase in oxidative stress biomarkers was detected in the heart tissue of BDL animals. Moreover, it was found that heart tissue mitochondrial indices of functionality were deteriorated in the BDL group. Tau treatment significantly decreased oxidative stress and improved mitochondrial function in the heart tissue of cirrhotic animals. These data provide clues for the involvement of mitochondrial impairment and oxidative stress in the pathogenesis of heart injury in BDL rats. On the other hand, Tau supplementation could serve as an effective ancillary treatment against BDL-associated heart injury. Mitochondrial regulating and antioxidative properties of Tau might play a fundamental role in its mechanism of protective effects in the heart tissue of BDL animals.

9.
Clin Exp Hepatol ; 6(2): 106-115, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32728627

RESUMO

Aim of the study: Acute or chronic live failure could result in hyperammonemia and hepatic encephalopathy (HE). HE is a clinical complication characterized by severe cognitive dysfunction and coma. The ammonium ion (NH4 +) is the most suspected toxic molecule involved in the pathogenesis of HE. NH4 + is a neurotoxic agent. Different mechanisms, including oxidative/nitrosative stress, inflammatory response, excitotoxicity, and mitochondrial impairment, are proposed for NH4 +-induced neurotoxicity. N-acetyl cysteine (NAC) is a well-known thiol-reductant and antioxidant agent. Several investigations also mentioned the positive effects of NAC on mitochondrial function. In the current study, the effect of NAC treatment on brain mitochondrial indices and energy status was investigated in an animal model of HE. Material and methods: Acetaminophen (APAP)-induced acute liver failure was induced by a single dose of the drug (800 mg/kg, i.p.) to C57BL/6J mice. Plasma and brain levels of NH4 + were measured. Then, brain mitochondria were isolated, and several indices, including mitochondrial depolarization, ATP level, lipid peroxidation, glutathione content, mitochondrial permeabilization, and dehydrogenase activity, were assessed. Results: A significant increase in plasma and brain NH4 + was evident in APAP-treated animals. Moreover, mitochondrial indices of functionality were impaired, and mitochondrial oxidative stress biomarkers were significantly increased in APAP-treated mice. It was found that NAC treatment (100, 200, and 400 mg/kg, i.p.) significantly mitigated mitochondrial impairment in the brain of APAP-treated animals. Conclusions: These data suggest the effects of NAC on brain mitochondrial function and energy status as a pivotal mechanism involved in its neuroprotective properties during HE.

10.
Toxicol Lett ; 330: 144-158, 2020 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-32422328

RESUMO

Cholestatic liver disease is a clinical complication with a wide range of etiologies. The liver is the primary organ influenced by cholestasis. Other organs, rather than the liver (e.g., kidneys), could also be affected by cholestatic liver disease. Cholestasis-induced renal injury is known as cholemic nephropathy (CN). Although the structural and functional alterations of the kidney in cholestasis have been well described, the cellular and molecular mechanisms of CN are not well understood. Some studies mentioned the role of oxidative stress and mitochondrial impairment in CN. Several cellular targets, including proteins, lipids, and DNA, could be affected by oxidative stress. Poly (ADP-Ribose) polymerase-1 (PARP-1) is an enzyme that its physiological activity plays a fundamental role in DNA repair. However, PARP-1 overexpression is associated with enhanced oxidative stress and cell death. The current study was designed to evaluate the role of PARP-1 activity in the pathogenesis of CN. Bile duct ligated (BDL) rats were treated with nicotinamide (NA) as a PARP-1 inhibitor. Kidney, urine, and plasma samples were collected at scheduled time intervals (3, 7, 14, and 28 days after BDL surgery). Serum and urine biomarkers of kidney injury, markers of oxidative stress and DNA damage, PARP-1 expression and activity in the kidney tissue, inflammatory response, renal fibrosis markers, and kidney histopathological alterations were assessed. Significant changes in the serum and urine biomarkers of kidney injury were evident in the BDL rats. Markers of oxidative stress were increased, and tissue ATP levels and antioxidant capacity were decreased in the kidney of cholestatic animals. A significant increase in PARP-1 expression and activity was evident in BDL rats (3, 7, 14, and 28 days after BDL). Moreover, inflammatory response (IL-1ß and TNF-α expression; and myeloperoxidase activity), renal tissue histopathological alterations, and kidney fibrosis (α-SMA and TGF-ß expression, as well as collagen deposition) were detected in cholestatic animals. It was found that the PARP-1 inhibitor, NA (50 and 100 mg/kg, i.p), significantly mitigated cholestasis-induced renal injury. The positive effects of NA were more significant at a lower dose and the early stage of CN. These data indicate a pathogenic role for PARP-1 overexpression in CN.

11.
Toxicol Mech Methods ; 30(6): 427-437, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32312132

RESUMO

Di-(2-ethylhexyl) phthalate (DEHP) and its main metabolite, monoethylhexyl phthalic acid (MEHP), are a serious threat to human and animals' health in the current century. However, their exact mechanism to induce nephrotoxicity is not clear. In the current study, we addressed toxic effects of MEHP and DEHP on embryonic human kidney cells (HEK-293 cell line) and kidney tissue of rats, respectively. In the HEK-293, MTT assay and oxidative stress parameters were measured after treatment with different concentrations of MEHP. For in vivo study, rats were treated with different doses of DEHP (50, 100, 200, 400 mg/kg) via gavage administration for 45 days. The renal function biomarkers (BUN and creatinine) were determined in serum of rats. Mitochondrial toxic parameters including MTT, mitochondrial membrane potential (MMP), mitochondrial swelling, and also oxidative stress parameters were measured in isolated kidney mitochondria. Histopathological effects of DEHP were also evaluated in rats' kidneys. We demonstrated that MEHP induced oxidative stress and cytotoxicity in HEK-293 cells in a concentration dependent manner. The administration of DEHP led to histopathological changes in kidney tissue, which concurred with BUN and creatinine alternations in serum of rats. The results of present study showed a significant mitochondrial dysfunction and oxidative stress confirmed by enhancement of mitochondrial swelling, mitochondrial reactive oxygen species (ROS) and malondialdehyde (MDA), and reduction of MMP and mitochondrial glutathione (GSH). Taken together, this study showed that DEHP/MEHP resulted in mitochondrial dysfunction and oxidative damage, which suggest a vital role of mitochondria in DEHP/MEHP-induced nephrotoxicity.


Assuntos
Dietilexilftalato/análogos & derivados , Nefropatias/induzido quimicamente , Rim/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Biomarcadores/sangue , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Dietilexilftalato/toxicidade , Células HEK293 , Humanos , Rim/metabolismo , Rim/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Dilatação Mitocondrial/efeitos dos fármacos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
12.
Cryobiology ; 95: 171-176, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32220594

RESUMO

Oxidative stress is believed to be an important cause of sperm damage during freezing. l-Carnitine (LC) may have the potential to improve sperm quality after frozen-thawed process. The present study aimed to investigate the effect of LC supplementation in cryoprotectant media of mouse epididymal sperm on post-thaw sperm quality and expression of apoptosis-related genes. Male BALB/cJ mice spermatozoa were cryopreserved in a cryoprotectant medium containing 2.5 or 5 mM LC. The untreated group was cryopreserved with the cryoprotectant medium only. Six months following cryopreservation, the samples were thawed and sperm quality parameters, chromatin and acrosome integrity, reactive oxygen species (ROS) and glutathione (GSH) levels, mitochondrial activity, and mRNA expression of Bax and Bcl-2 were assessed. The results demonstrated that the concentration of 5 mM LC in cryoprotectant media exhibited higher values for the sperm quality parameters and integrity of chromatin and acrosome in post-thaw spermatozoa than those of the untreated group. Furthermore, sperm ROS levels decreased while GSH and mitochondrial activity levels increased in 5 mM LC group compared to those in the untreated group (P < 0.01). In 5 mM LC-treated group, Bax was down-regulated (P < 0.05) while Bcl-2 was up-regulated (P < 0.001) compared to the untreated group. Collectively, LC supplementation of cryoprotectant medium improved the quality of frozen-thawed mouse epididymal spermatozoa, as showed reduced ROS level and Bax expression as well as increased GSH, mitochondrial activity, and Bcl-2 expression.


Assuntos
Criopreservação , Preservação do Sêmen , Acrossomo , Animais , Apoptose , Carnitina/farmacologia , Cromatina , Criopreservação/métodos , Humanos , Masculino , Camundongos , Estresse Oxidativo , Preservação do Sêmen/veterinária , Motilidade Espermática , Espermatozoides
13.
Life Sci ; 248: 117452, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32088214

RESUMO

AIMS: The aim of this study was to elucidate the signaling pathway involved in the anti-aging effect of tropisetron and to clarify whether it affects mitochondrial oxidative stress, apoptosis and inflammation in the aging mouse brain by upregulating Sirtuin 1 or silent information regulator 1 (SIRT1). MATERIALS AND METHODS: Aging was induced by d-galactose (DG) at the dose of 200 mg/kg body weight/day subcutaneously injected to male mice for six weeks. Tropisetron was simultaneously administered intraperitoneally once a day at three various doses (1, 3 and 5 mg/kg body weight). Oxidative stress and mitochondrial dysfunction markers were evaluated. Nitric oxide (NO) and pro-inflammatory cytokines levels including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were studied. Besides, the expressions of apoptosis-associated genes (Bax and Bcl-2) and the aging-related gene (SIRT1) were determined by the real time polymerase chain reaction (RT-PCR). In addition, histopathological alterations were assessed. KEY FINDINGS: Tropisetron reversed the induction of oxidative damage, mitochondrial dysfunction and overproduction of inflammatory mediators induced by DG in the brain tissue. In addition, tropisetron suppressed DG-induced apoptosis and found to significantly elevate SIRT1 gene expression. Besides, tropisetron could markedly alleviate DG-induced abnormal changes in the brain morphology. SIGNIFICANCE: Tropisetron exhibited anti-aging effects in the context of DG-induced senescence in mouse brain through various pathways. Our results suggest that tropisetron may attenuate DG-induced brain aging via SIRT1 signaling activation.


Assuntos
Envelhecimento/efeitos dos fármacos , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia , Sirtuína 1/genética , Tropizetrona/farmacologia , Envelhecimento/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Encéfalo/metabolismo , Encéfalo/patologia , Esquema de Medicação , Galactose/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação , Injeções Intraperitoneais , Injeções Subcutâneas , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
14.
Anticancer Agents Med Chem ; 19(17): 2140-2153, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31736448

RESUMO

BACKGROUND: Green synthesis of silver nanoparticles (AgNPs) is limited to produce AgNPs with only relatively low concentrations, and is unsuitable for large-scale productions. The use of Myrtus communis (MC) leaf methanolic extract (rich in hydrolyzable tannins) has been recommended to resolve the issues related to the aggregation of nanoparticles at high concentrations of silver ions with added facet of antioxidant properties. METHODS: The produced highly concentrated MC-AgNPs were characterized by using imaging and spectroscopic methods. Subsequently, antioxidant, anticancer and antifungal activities of the nanoparticles were evaluated. RESULTS: The thermogravimetric analysis and energy dispersive spectroscopy quantitative results suggested that the nanoparticles are biphasic in nature (bio-molecule + Ag0) and layered in structure, suggesting the formation of nanoparticles through a different mechanism than those described in the literature. MC-AgNPs showed greater scavenging activity of nitric oxide and iron (II) chelating ability than the extract. It also showed good reducing power compared to the standard antioxidant. Remarkable anticancer activity of MC-AgNPs (IC50 = 5.99µg/mL) was found against HCT-116 (human colon carcinoma) cell lines after 24h exposure with a therapeutic index value 2-fold higher than the therapeutic index of standard doxorubicin. Furthermore, distinct antifungal activity (MIC = 4µg/mL) was found against Candida krusei. CONCLUSION: The current method outperforms the existing methods because it produces a large amount of multifunctional nanoscale hybrid materials more efficiently using natural sources; thus, it may be used for diverse biomedical applications.


Assuntos
Antifúngicos/farmacologia , Antioxidantes/farmacologia , Candida/efeitos dos fármacos , Nanopartículas/química , Prata/farmacologia , Antifúngicos/química , Antioxidantes/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Íons/química , Íons/farmacologia , Testes de Sensibilidade Microbiana , Oxirredução , Prata/química
15.
Curr Pharm Des ; 25(39): 4192-4207, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31721699

RESUMO

BACKGROUND: Most of the anticancer chemotherapies are hampered via the development of multidrug resistance (MDR), which is the resistance of tumor cells against cytotoxic effects of multiple chemotherapeutic agents. Overexpression and/or over-activation of ATP-dependent drug efflux transporters is a key mechanism underlying MDR development. Moreover, enhancement of drug metabolism, changes in drug targets and aberrant activation of the main signaling pathways, including Wnt, Akt and NF-κB are also responsible for MDR. METHODS: In this study, we have reviewed the roles of Wnt signaling in MDR as well as its potential therapeutic significance. Pubmed and Scopus have been searched using Wnt, ß-catenin, cancer, MDR and multidrug resistance as keywords. The last search was done in March 2019. Manuscripts investigating the roles of Wnt signaling in MDR or studying the modulation of MDR through the inhibition of Wnt signaling have been involved in the study. The main focus of the manuscript is regulation of MDR related transporters by canonical Wnt signaling pathway. RESULT AND CONCLUSION: Wnt signaling has been involved in several pathophysiological states, including carcinogenesis and embryonic development. Wnt signaling is linked to various aspects of MDR including P-glycoprotein and multidrug resistance protein 1 regulation through its canonical pathways. Aberrant activation of Wnt/ß- catenin signaling leads to the induction of cancer MDR mainly through the overexpression and/or over-activation of MDR related transporters. Accordingly, Wnt/ß-catenin signaling can be a potential target for modulating cancer MDR.


Assuntos
Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Neoplasias/metabolismo , Via de Sinalização Wnt , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Linhagem Celular Tumoral , Humanos , Neoplasias/tratamento farmacológico
16.
Int J Reprod Biomed ; 17(5)2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31435617

RESUMO

Background: Diabetes mellitus affects male reproductive system that is known to cause male infertility. Objective: The aim of the present study was to assess the effects of L-carnitine (LC) on sperm parameters, apoptosis of spermatogenic cells and testis histopathology in Streptozotocin-induced diabetic Rats. Materials and Methods: The study was carried out on 36 male Wistar adult rats (220 ± 30 gr) randomly divided into six groups (n = 6/each). 1 (Control); 2 (LC 100 mg/kg); 3 (Diabetic); 4, 5, and 6 (Diabetic + LC 50 or 100 or 200 mg/kg, respectively). Daily injections were administered intraperitoneally for 48 days. Then, rats were sacrificed, left testis and epididymis were harvested for sperm analysis and histopathology, morphometric and spermatogenesis assessments, and Tunnel assay. Results: L-carnitine in group 6 significantly decreased blood glucose level (p < 0.01) in comparison with group 3. L-carnitine in groups 5 and 6 significantly (p < 0.001) and dose-dependently increased the count, motility, viability, maturity, and chromatin quality of sperm and decreased the abnormal morphology of sperm in comparison with group 3. In groups 4, 5, and particularly 6, in comparison with group 3, there has been a significant difference in the increase of seminiferous tubule diameter, germinal epithelium height (p < 0.001), maturity quality of the seminiferous tubules (p < 0.001), decrease apoptosis of spermatogenic cells (p < 0.001), and testis tissue histopathological complications. Conclusion: The data obtained from the present study suggest that in the diabetic rats, LC decreases serum glucose level, improves the diameter and thickness of the epithelium of spermatogenic cells, reduces germ cells' apoptosis, and improves epididymal sperm parameters. Therefore, it seems that LC plays an effective role in diabetes-induced infertility.

17.
Drug Chem Toxicol ; : 1-7, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31368376

RESUMO

Tramadol (TR) is an analgesic drug used to treat moderate-to-severe pain but it induces seizure even at therapeutic doses. The exact mechanism of TR-inducing seizure is not clear but inhibition of the serotonin, GABA, and nitrous oxide (NOS) pathways are the commonly proposed mechanisms. Adenosinergic system has a crucial function in the modulation of seizure. Also, oxidative damage is an unavoidable effect of the seizure. This study was conducted to evaluate the role of the adenosinergic system on the seizure and oxidative stress biomarkers induced by TR using antagonist of the adenosinergic receptors in the Albino mice. For that purpose, generated clonic seizure, as seizure threshold, was evaluated by TR. Caffeine (CAF; 8 mg/kg, i.p.), a nonselective antagonist of adenosine receptors, was administered 1 hour before the seizure induction. The seizure threshold significantly increased by CAF-treated group when compared to TR group (p < 0.001). Oxidative stress biomarkers such as reactive oxygen species, protein carbonyl content, and lipid peroxidation significantly decreased and glutathione content significantly increased by CAF in brain mitochondria compared to the TR group, whereas oxidative biomarkers significantly increased in the TR group compared to the control group. The results of the present study suggested that the adenosinergic system is involved in seizure induced by TR and meanwhile, inhibition of adenosine receptors can decrease the TR seizure threshold and also decrease the induced oxidative damage in the brain mitochondria.

18.
J Mater Chem B ; 7(34): 5211-5221, 2019 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-31364687

RESUMO

Microbial exopolysaccharides (EPSs) have recently served as an efficient substrate for the production of biocompatible metal nanoparticles (NPs) given their favorable stabilizing and reducing properties due to the presence of polyanionic functional groups in their structure. In the present work, Pantoea sp. BCCS 001 GH was used to produce EPS-stabilized biogenic Fe NPs as a complex through a novel biosynthesis reaction. Physicochemical characterization of the EPS-Fe complex was performed, indicating high thermal stability, desirable magnetic properties due to the uniform distribution of the Fe NPs with the average size of ∼10 nm and spherical shape within the EPS matrix. In addition, the in vivo toxicity of the EPS-stabilized Fe NPs was evaluated to investigate their potential for the treatment of iron deficiency anemia. Biological blood parameters and organ histology studies confirmed very high safety of the biosynthesized composite, making EPS-Fe a suitable candidate with an economical and environment friendly synthesis method for a wide spectrum of potential fields in medicine.


Assuntos
Sequestradores de Radicais Livres/farmacologia , Compostos de Ferro/farmacologia , Nanopartículas/química , Inquéritos Nutricionais , Pantoea/metabolismo , Polissacarídeos/farmacologia , Administração Oral , Animais , Sobrevivência Celular/efeitos dos fármacos , Suplementos Nutricionais , Sequestradores de Radicais Livres/administração & dosagem , Sequestradores de Radicais Livres/metabolismo , Humanos , Compostos de Ferro/administração & dosagem , Compostos de Ferro/metabolismo , Células MCF-7 , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem , Nanopartículas/metabolismo , Tamanho da Partícula , Polissacarídeos/administração & dosagem , Polissacarídeos/biossíntese , Propriedades de Superfície
19.
Life Sci ; 232: 116677, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31340166

RESUMO

AIMS: Senescence is a state ensuing aging to eliminate age-associated damage with an irreversible cell-cycle arrest mechanism, which is historically believed to be one of the tumor responses to therapy. Doxorubicin as an anti-cancer drug has been used in cancer treatment for a long time. Liposomal doxorubicin (Ldox) is a liposomal formulation of doxorubicin, which increases the doxorubicin permanency. The aim of this study was to examine the toxicity of these two formulations by comparing them in terms of their ability to induce cellular senescence. MAIN METHODS: The study groups included a control group, three DOX (0.75, 0.5, 0.1 mg/kg/BW) and three Ldox groups (0.1, 0.05, 0.025 mg/kg/BW). Heart tissues were studied regarding oxidative stress assessment, mitochondrial function, inflammatory markers and biochemical and histopathological evaluation. Real-Time PCR was used for P53 and SA ß-gal expression. KEY FINDINGS: Based on the results, the highest doses of Dox and Ldox (0.75 and 0.1 mg/kg/BW respectively) significantly increased the level of inflammatory markers and according to other factors especially p53 and SA ß-gal expression, both were able to induce senescence but the changes in Ldox were less tangible than the Dox.


Assuntos
Senescência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NF-kappa B/metabolismo , Animais , Biomarcadores/metabolismo , Doxorrubicina/análogos & derivados , Glutationa Peroxidase/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Polietilenoglicóis/farmacologia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Proteína Supressora de Tumor p53/metabolismo
20.
Arh Hig Rada Toksikol ; 70(2): 74-89, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31246571

RESUMO

Pyrethroids are a class of synthetic insecticides that are used widely in and around households to control the pest. Concerns about exposure to this group of pesticides are now mainly related to their neurotoxicity and nigrostriatal dopaminergic neurodegeneration seen in Parkinson's disease. The main neurotoxic mechanisms include oxidative stress, inflammation, neuronal cell loss, and mitochondrial dysfunction. The main neurodegeneration targets are ion channels. However, other receptors, enzymes, and several signalling pathways can also participate in disorders induced by pyrethroids. The aim of this review is to elucidate the main mechanisms involved in neurotoxicity caused by pyrethroids deltamethrin, permethrin, and cypermethrin. We also review common targets and pathways of Parkinson's disease therapy, including Nrf2, Nurr1, and PPARγ, and how they are affected by exposure to pyrethroids. We conclude with possibilities to be addressed by future research of novel methods of protection against neurological disorders caused by pesticides that may also find their use in the management/treatment of Parkinson's disease.


Assuntos
Antitoxinas/uso terapêutico , Inseticidas/toxicidade , Síndromes Neurotóxicas/tratamento farmacológico , Nitrilas/toxicidade , Doença de Parkinson/tratamento farmacológico , Permetrina/toxicidade , Piretrinas/toxicidade , Humanos , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/efeitos dos fármacos , PPAR alfa/efeitos dos fármacos , Doença de Parkinson/etiologia
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