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1.
Molecules ; 26(16)2021 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-34443393

RESUMO

Zizyphus lotus L. (Desf.) (Z. lotus) is a medicinal plant largely distributed all over the Mediterranean basin and is traditionally used by Moroccan people to treat many illnesses, including kidney failure. The nephrotoxicity of gentamicin (GM) has been well documented in humans and animals, although the preventive strategies against it remain to be studied. In this investigation, we explore whether the extract of Zizyphus lotus L. (Desf.) Fruit (ZLF) exhibits a protective effect against renal damage produced by GM. Indeed, twenty-four Wistar rats were separated into four equal groups of six each (♂/♀ = 1). The control group was treated orally with distilled water (10 mL/kg); the GM treated group received distilled water (10 mL/kg) and an intraperitoneal injection of GM (80 mg/kg) 3 h after; and the treated groups received ZLF extract orally at the doses 200 or 400 mg/kg and injected intraperitoneally with the GM. All treatments were given daily for 14 days. At the end of the experiment, the biochemical parameters and the histological observation related the kidney function was explored. ZLF treatment has significantly attenuated the nephrotoxicity induced by the GM. This effect was indicated by its capacity to decrease significantly the serum creatinine, uric acid, urea, alkaline phosphatase, gamma-glutamyl-transpeptidase, albumin, calcium, sodium amounts, water intake, urinary volume, and relative kidney weight. In addition, this effect was also shown by the increase in the creatinine clearance, urinary creatinine, uric acid, and urea levels, weight gain, compared to the rats treated only with the GM. The hemostasis of oxidants/antioxidants has been significantly improved with the treatment of ZLF extract, which was shown by a significant reduction in malondialdehydes levels. Histopathological analysis of renal tissue was correlated with biochemical observation. Chemical analysis by HPLC-DAD showed that the aqueous extract of ZLF is rich in phenolic compounds such as 3-hydroxycinnamic acid, catechin, ferulic acid, gallic acid, hydroxytyrosol, naringenin, p- coumaric Acid, quercetin, rutin, and vanillic acid. In conclusion, ZLF extract improved the nephrotoxicity induced by GM, through the improvement of the biochemical and histological parameters and thus validates its ethnomedicinal use.


Assuntos
Injúria Renal Aguda/patologia , Citoproteção/efeitos dos fármacos , Frutas/química , Gentamicinas/efeitos adversos , Rim/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ziziphus/química , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/prevenção & controle , Animais , Modelos Animais de Doenças , Rim/metabolismo , Rim/patologia , Ratos , Ratos Wistar
2.
Chem Biol Interact ; 345: 109572, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34217687

RESUMO

Oxidized low-density lipoprotein (ox-LDL) not only causes hyperlipidemia and contributes to atherosclerosis but also induces the endothelial dysfunction that leads to cardiovascular diseases. The nuclear factor-kappa B (NF-κB) pathway plays a key role in many chronic disorders and is a transcriptional factor in various inflammatory responses. The present study aimed to investigate the synergistic effects of pelargonic acid vanillylamide (PAVA) and rosuvastatin (RSV) on ox-LDL-induced inflammatory responses in human vascular endothelial cells (HUV-EC-C). HUV-EC-C were pretreated with PAVA or RSV and their combination for 2 h followed by ox-LDL for 24 h. The MTT assay was used to measure mitochondrial function. The DCFH-DA assay was used to evaluate oxidative phosphorylation, and western blotting was used to measured NF-κB/NLRP3 and related signaling pathways in HUV-EC-C. Ox-LDL induced lectin-type oxidized LDL receptor 1 (LOX-1) expression, NADPH oxidase 4 activation, and the overexpression of reactive oxygen species, which were inhibited by pretreatment with the combination of PAVA and RSV. Moreover, PAVA and RSV inhibited ox-LDL-induced NF-κBp65 activation. Ox-LDL induced NF-κB/NLRP3 pathway activation by inducing C-reactive protein expression, NLRP3 activation, caspase-1 activation, and IL-1ß secretion, which were inhibited by pretreatment with the combination of PAVA and RSV. The combination of PAVA and RSV reduced ox-LDL-induced recruitment of monocytes to the site of inflammation, inhibited activation of the NLRP3 inflammasome, and ameliorated the impairment of cell-cell junctions through the NF-κB pathway. Our results suggest that the synergistic effects of PAVA and RSV provide a novel mechanism for the treatment of cardiovascular diseases.


Assuntos
Benzilaminas/farmacologia , Citoproteção/efeitos dos fármacos , Ácidos Graxos/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Junções Intercelulares/efeitos dos fármacos , Lipoproteínas LDL/farmacologia , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Caspase 1/metabolismo , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamassomos/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202670

RESUMO

Astragalus membranaceus is a famous herb found among medicinal and food plants in East and Southeastern Asia. The Nrf2-ARE assay-guided separation of an extract from Jing liqueur led to the identification of a nontoxic Nrf2 activator, methylnissolin-3-O-ß-d-glucopyranoside (MNG, a component of A. membranaceus). Nrf2 activation by MNG has not been reported before. Using Western Blot, RT-qPCR and imaging, we investigated the cytoprotective effect of MNG against hydrogen peroxide-induced oxidative stress. MNG induced the expression of Nrf2, HO-1 and NQO1, accelerated the translocation of Nrf2 into nuclei, and enhanced the phosphorylation of AKT. The MNG-induced expression of Nrf2, HO-1, and NQO1 were abolished by Nrf2 siRNA, while the MNG-induced expression of Nrf2 and HO-1 was abated and the AKT phosphorylation was blocked by LY294002 (a PI3K inhibitor). MNG reduced intracellular ROS generation. However, the protection of MNG against the H2O2 insult was reversed by Nrf2 siRNA with decreased cell viability. The enhancement of Nrf2 and HO-1 by MNG upon H2O2 injury was reduced by LY294002. These data showed that MNG protected EA.hy926 cells against oxidative damage through the Nrf2/HO-1 and at least partially the PI3K/Akt pathways.


Assuntos
Astragalus propinquus/química , Citoproteção/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Cromonas , Células Hep G2 , Humanos , Morfolinas , Compostos Fitoquímicos/química
4.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203861

RESUMO

Circulating hemopexin is the primary protein responsible for the clearance of heme; therefore, it is a systemic combatant against deleterious inflammation and oxidative stress induced by the presence of free heme. This role of hemopexin is critical in hemolytic pathophysiology. In this review, we outline the current research regarding how the dynamic activity of hemopexin is implicated in sickle cell disease, which is characterized by a pathological aggregation of red blood cells and excessive hemolysis. This pathophysiology leads to symptoms such as acute kidney injury, vaso-occlusion, ischemic stroke, pain crises, and pulmonary hypertension exacerbated by the presence of free heme and hemoglobin. This review includes in vivo studies in mouse, rat, and guinea pig models of sickle cell disease, as well as studies in human samples. In summary, the current research indicates that hemopexin is likely protective against these symptoms and that rectifying depleted hemopexin in patients with sickle cell disease could improve or prevent the symptoms. The data compiled in this review suggest that further preclinical and clinical research should be conducted to uncover pathways of hemopexin in pathological states to evaluate its potential clinical function as both a biomarker and therapy for sickle cell disease and related hemoglobinopathies.


Assuntos
Anemia Falciforme/patologia , Anemia Falciforme/fisiopatologia , Citoproteção , Hemopexina/metabolismo , Animais , Humanos , Imunomodulação , Lipoproteínas/metabolismo , Microvasos/patologia
5.
Molecules ; 26(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208534

RESUMO

Endothelial cell dysfunction is considered to be one of the major causes of vascular complications in diabetes. Polyphenols are known as potent antioxidants that can contribute to the prevention of diabetes. Corn silk has been reported to contain polyphenols and has been used in folk medicine in China for the treatment of diabetes. The present study aims to investigate the potential protective role of the phenolic-rich fraction of corn silk (PRF) against injuries to vascular endothelial cells under high glucose conditions in vitro and in vivo. The protective effect of PRF from high glucose toxicity was investigated using human umbilical vein endothelial cells (HUVECs). The protective effect of PRF was subsequently evaluated by using in vivo methods in streptozotocin (STZ)-induced diabetic rats. Results showed that the PRF significantly reduced the cytotoxicity of glucose by restoring cell viability in a dose-dependent manner. PRF was also able to prevent the histological changes in the aorta of STZ-induced diabetic rats. Results suggested that PRF might have a beneficial effect on diabetic patients and may help to prevent the development and progression of diabetic complications such as diabetic nephropathy and atherosclerosis.


Assuntos
Células Endoteliais/efeitos dos fármacos , Polifenóis/farmacologia , Zea mays/metabolismo , Animais , Antioxidantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , China , Citoproteção/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Células Endoteliais/metabolismo , Glucose/efeitos adversos , Glucose/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Masculino , Extratos Vegetais/farmacologia , Polifenóis/química , Ratos , Ratos Sprague-Dawley , Estreptozocina/farmacologia
6.
Int J Mol Sci ; 22(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299209

RESUMO

Misfolded amyloid beta (Aß) peptides aggregate and form neurotoxic oligomers. Membrane and mitochondrial damages, calcium dysregulation, oxidative stress, and fibril deposits are among the possible mechanisms of Aß cytotoxicity. Galantamine (GAL) prevents apoptosis induced by Aß mainly through the ability to stimulate allosterically the α7 nAChRs and to regulate the calcium cytosolic concentration. Here, we examined the cytoprotective effects of two GAL derivatives, namely compounds 4b and 8, against Aß cytotoxicity on the human neuroblastoma cell line SH-SY5Y. The protective effects were tested at simultaneous administration, pre-incubation and post-incubation, with Aß. GAL and curcumin (CU) were used in the study as reference compounds. It was found that 4b protects cells in a similar mode as GAL, while compound 8 and CU potentiate the toxic effects of Aß. Allosteric stimulation of α7 nAChRs is suggested as a possible mechanism of the cytoprotectivity of 4b. These and previous findings characterize 4b as a prospective non-toxic multi-target agent against neurodegenerative disorders with inhibitory activity on acetylcholinesterase, antioxidant, and cytoprotective properties.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Curcumina/química , Galantamina/química , Neuroblastoma/tratamento farmacológico , Substâncias Protetoras/farmacologia , Acetilcolinesterase/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antioxidantes/química , Inibidores da Colinesterase/química , Curcumina/farmacologia , Citoproteção , Galantamina/farmacologia , Humanos , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Substâncias Protetoras/química , Células Tumorais Cultivadas
7.
Molecules ; 26(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199157

RESUMO

The influence of p-terphenyl polyketides 1-3 from Aspergillus candidus KMM 4676 and cerebroside flavuside B (4) from Penicillium islandicum (=Talaromyces islandicus) against the effect of neurotoxins, rotenone and paraquat, on Neuro-2a cell viability by MTT and LDH release assays and intracellular ROS level, as well as DPPH radical scavenging activity, was investigated. Pre-incubation with compounds significantly diminished the ROS level in rotenone- and paraquat-treated cells. It was shown that the investigated polyketides 1-3 significantly increased the viability of rotenone- and paraquat-treated cells in two of the used assays but they affected only the viability of paraquat-treated cells in the LDH release assay. Flavuside B statistically increased the viability of paraquat-treated cells in both MTT and LDH release assays, however, it increased the viability of rotenone-treated cells in the LDH release assay. Structure-activity relationships for p-terphenyl derivatives, as well as possible mechanisms of cytoprotective action of all studied compounds, were discussed.


Assuntos
Aspergillus/química , Citoproteção/efeitos dos fármacos , Glicoesfingolipídeos/farmacologia , Neuroblastoma/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/toxicidade , Policetídeos/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Herbicidas/toxicidade , Inseticidas/toxicidade , Camundongos , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Fármacos Neuroprotetores/química , Paraquat/toxicidade , Policetídeos/química , Espécies Reativas de Oxigênio , Rotenona/toxicidade
8.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299059

RESUMO

BACKGROUND: Doxorubicin (Dox) is a first-line treatment for triple negative breast cancer (TNBC), but its use may be limited by its cardiotoxicity mediated by the production of reactive oxygen species. We evaluated whether vitamin D may prevent Dox-induced cardiotoxicity in a mouse TNBC model. METHODS: Female Balb/c mice received rodent chow with vitamin D3 (1500 IU/kg; vehicle) or chow supplemented with additional vitamin D3 (total, 11,500 IU/kg). the mice were inoculated with TNBC tumors and treated with intraperitoneal Dox (6 or 10 mg/kg). Cardiac function was evaluated with transthoracic echocardiography. The cardiac tissue was evaluated with immunohistochemistry and immunoblot for levels of 4-hydroxynonenal, NAD(P)H quinone oxidoreductase (NQO1), C-MYC, and dynamin-related protein 1 (DRP1) phosphorylation. RESULTS: At 15 to 18 days, the mean ejection fraction, stroke volume, and fractional shortening were similar between the mice treated with vitamin D + Dox (10 mg/kg) vs. vehicle but significantly greater in mice treated with vitamin D + Dox (10 mg/kg) vs. Dox (10 mg/kg). Dox (10 mg/kg) increased the cardiac tissue levels of 4-hydroxynonenal, NQO1, C-MYC, and DRP1 phosphorylation at serine 616, but these increases were not observed with vitamin D + Dox (10 mg/kg). A decreased tumor volume was observed with Dox (10 mg/kg) and vitamin D + Dox (10 mg/kg). CONCLUSIONS: Vitamin D supplementation decreased Dox-induced cardiotoxicity by decreasing the reactive oxygen species and mitochondrial damage, and did not decrease the anticancer efficacy of Dox against TNBC.


Assuntos
Cardiotoxicidade/prevenção & controle , Citoproteção/efeitos dos fármacos , Doxorrubicina/toxicidade , Substâncias Protetoras/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Vitamina D/farmacologia , Vitaminas/farmacologia , Animais , Antibióticos Antineoplásicos/toxicidade , Cardiotoxicidade/etiologia , Cardiotoxicidade/patologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias de Mama Triplo Negativas/induzido quimicamente , Neoplasias de Mama Triplo Negativas/patologia
9.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198548

RESUMO

Inflammation in the tumor microenvironment has been shown to promote disease progression in pancreatic ductal adenocarcinoma (PDAC); however, the role of macrophage metabolism in promoting inflammation is unclear. Using an orthotopic mouse model of PDAC, we demonstrate that macrophages from tumor-bearing mice exhibit elevated glycolysis. Macrophage-specific deletion of Glucose Transporter 1 (GLUT1) significantly reduced tumor burden, which was accompanied by increased Natural Killer and CD8+ T cell activity and suppression of the NLRP3-IL1ß inflammasome axis. Administration of mice with a GLUT1-specific inhibitor reduced tumor burden, comparable with gemcitabine, the current standard-of-care. In addition, we observe that intra-tumoral macrophages from human PDAC patients exhibit a pronounced glycolytic signature, which reliably predicts poor survival. Our data support a key role for macrophage metabolism in tumor immunity, which could be exploited to improve patient outcomes.


Assuntos
Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/patologia , Citoproteção , Glicólise , Macrófagos/metabolismo , Neoplasias Pancreáticas/patologia , Adenocarcinoma/imunologia , Animais , Carcinoma Ductal Pancreático/imunologia , Proliferação de Células/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transportador de Glucose Tipo 1/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Hidroxibenzoatos/farmacologia , Inflamação/patologia , Interleucina-1beta/metabolismo , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neoplasias Pancreáticas/imunologia , Análise de Sobrevida , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Carga Tumoral/efeitos dos fármacos
10.
Int J Cancer ; 149(7): 1463-1472, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34109630

RESUMO

Chemotherapy-induced myelosuppression is an acute, dose-limiting toxicity of chemotherapy regimens used in the treatment of extensive-stage small cell lung cancer (ES-SCLC). Trilaciclib protects haematopoietic stem and progenitor cells from chemotherapy-induced damage (myeloprotection). To assess the totality of the myeloprotective benefits of trilaciclib, including analysis of several clinically relevant but low-frequency events, an exploratory composite endpoint comprising five major adverse haematological events (MAHE) was prospectively defined: all-cause hospitalisations, all-cause chemotherapy dose reductions, febrile neutropenia (FN), prolonged severe neutropenia (SN) and red blood cell (RBC) transfusions on/after Week 5. MAHE and its individual components were assessed in three randomised, double-blind, placebo-controlled Phase 2 trials in patients receiving a platinum/etoposide or topotecan-containing chemotherapy regimen for ES-SCLC and in data pooled from the three trials. A total of 242 patients were randomised across the three trials (trilaciclib, n = 123; placebo, n = 119). In the individual trials and the pooled analysis, administering trilaciclib prior to chemotherapy resulted in a statistically significant reduction in the cumulative incidence of MAHE compared to placebo. In the pooled analysis, the cumulative incidences of all-cause chemotherapy dose reductions, FN, prolonged SN and RBC transfusions on/after Week 5 were significantly reduced with trilaciclib vs placebo; however, no significant difference was observed in rates of all-cause hospitalisations. Additionally, compared to placebo, trilaciclib significantly extended the amount of time patients remained free of MAHE. These data support the myeloprotective benefits of trilaciclib and its ability to improve the overall safety profile of myelosuppressive chemotherapy regimens used to treat patients with ES-SCLC.


Assuntos
Citoproteção , Doenças Hematológicas/prevenção & controle , Neoplasias Pulmonares/tratamento farmacológico , Células Mieloides/efeitos dos fármacos , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Idoso , Método Duplo-Cego , Feminino , Seguimentos , Doenças Hematológicas/induzido quimicamente , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Carcinoma de Pequenas Células do Pulmão/patologia
11.
Molecules ; 26(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071241

RESUMO

Amphipterygium adstringens (cuachalalate) contains anacardic acids (AAs) such as 6-pentadecyl salicylic acid (6SA) that show immunomodulatory and antitumor activity with minimal or no secondary adverse effects. By contrast, most chemotherapeutic agents, such as 5-fluorouracil (5-FU) and carboplatin (CbPt), induce myelosuppression and leukopenia. Here, we investigated the myeloprotective and antineoplastic potential of an AA extract or the 6SA as monotherapy or in combination with commonly used chemotherapeutic agents (5-FU and CbPt) to determine the cytoprotective action of 6SA on immune cells. Treatment of Balb/c breast tumor-bearing female mice with an AA mixture or 6SA did not induce the myelosuppression or leukopenia observed with 5-FU and CbPt. The co-administration of AA mixture or isolated 6SA with 5-FU or CbPt reduced the apoptosis of circulating blood cells and bone marrow cells. Treatment of 4T1 breast tumor-bearing mice with the AA mixture or 6SA reduced tumor growth and lung metastasis and increased the survival rate compared with monotherapies. An increased effect was observed in tumor reduction with the combination of 6SA and CbPt. In conclusion, AAs have important myeloprotective and antineoplastic effects, and they can improve the efficiency of chemotherapeutics, thereby protecting the organism against the toxic effects of drugs such as 5-FU and CbPt.


Assuntos
Ácidos Anacárdicos/química , Carboplatina/farmacologia , Fluoruracila/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Anacardiaceae , Ácidos Anacárdicos/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose , Células da Medula Óssea/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Citoproteção , Modelos Animais de Doenças , Feminino , Hexanos/química , Leucócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Casca de Planta/metabolismo
12.
Aging (Albany NY) ; 13(11): 15353-15365, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34086605

RESUMO

Blood brain barrier (BBB) dysfunction developed with aging is related to brain microvascular endothelial cells (BMECs) injury and losses of tight junctions (TJs). In the present study, we found that Alisol A 24-acetate (AA), a natural compound frequently used as treatment against vascular diseases was essential for BMECs injury and TJs degradation. Our experimental results showed that AA enhanced cell viability and increased zonula occludens-1 (ZO-1), claudin-5, and occludin expression in the oxygen-glucose deprivation (OGD)-induced BMECs. The exploration of the underlying mechanism revealed that AA restrained miR-92a-3p, a noncoding RNA involved in endothelial cells senescence and TJs impairment. To test the role of the miR-92a-3p in BMECs, the cells were transfected with miR-92a-3p mimics and inhibitor. The results showed that miR-92a-3p mimics inhibited cell viability and elevated lactate dehydrogenase (LDH) levels as well as suppressed ZO-1, claudin-5 and occludin expression, while the miR-92a-3p inhibitor reversed the above results. These findings were similar to the therapeutic effects of AA in the OGD-induced BMECs. Bioinformatics analysis and dual-luciferase assay confirmed ZO-1 and occludin were the target genes of miR-92a-3p mediated AA protective roles. In summary, the data demonstrated that AA protected against BMECs damage and TJs loss through the inhibition of miR-92a-3p expression. This provided evidence for AA application in aging-associated BBB protection.


Assuntos
Encéfalo/irrigação sanguínea , Colestenonas/farmacologia , Citoproteção/efeitos dos fármacos , Células Endoteliais/patologia , MicroRNAs/metabolismo , Microvasos/patologia , Junções Íntimas/metabolismo , Animais , Sequência de Bases , Linhagem Celular , Permeabilidade da Membrana Celular/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colestenonas/química , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/deficiência , L-Lactato Desidrogenase/metabolismo , Camundongos , MicroRNAs/genética , Oxigênio , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Junções Íntimas/genética , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/efeitos dos fármacos
13.
ACS Biomater Sci Eng ; 7(7): 3075-3081, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34133131

RESUMO

Mammalian cells are promising agents for cell therapy, diagnostics, and drug delivery. For full utilization of the cells, development of an exoskeleton may be beneficial to protecting the cells against the environmental stresses and cytotoxins to which they are susceptible. We report here a rapid single-step method for growing metal-organic framework (MOF) exoskeletons on a mammalian cell surface under cytocompatible conditions. The MOF exoskeleton coating on the mammalian cells was developed via a one-pot biomimetic mineralization process. With the exoskeleton on, the individual cells were successfully protected against cell protease (i.e., Proteinase K), whereas smaller-sized nutrient transport across the exoskeleton was maintained. Moreover, vital cellular activities mediated by transmembrane GLUT transporter proteins were also unaffected by the MOF exoskeleton formation on the cell surfaces. Altogether, this ability to control the access of specific molecules to a single cell through the porous exoskeleton, along with the cytoprotection provided, should be valuable for biomedical applications of mammalian cells.


Assuntos
Estruturas Metalorgânicas , Animais , Citoproteção , Porosidade , Proteínas
14.
Int J Nanomedicine ; 16: 3707-3724, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34103912

RESUMO

Introduction: Intracellular delivery of molecules is central to applications in biotechnology, medicine, and basic research. Nanoparticle-mediated photoporation using carbon black nanoparticles exposed to pulsed, near-infrared laser irradiation offers a physical route to create transient cell membrane pores, enabling intracellular delivery. However, nanoparticle-mediated photoporation, like other physical intracellular delivery technologies, necessitates a trade-off between achieving efficient uptake of exogenous molecules and maintaining high cell viability. Methods: In this study, we sought to shift this balance by adding serum to cells during nanoparticle-mediated photoporation as a viability protectant. DU-145 prostate cancer cells and human dermal fibroblasts were exposed to laser irradiation in the presence of carbon black (CB) nanoparticles and other formulation additives, including fetal bovine serum (FBS) and polymers. Results: Our studies showed that FBS can protect cells from viability loss, even at high-fluence laser irradiation conditions that lead to high levels of intracellular delivery in two different mammalian cell types. Further studies revealed that full FBS was not needed: viability protection was achieved with denatured FBS, with just the high molecular weight fraction of FBS (>30 kDa), or even with individual proteins like albumin or hemoglobin. Finally, we found that viability protection was also obtained using certain neutral water-soluble polymers, including Pluronic F127, polyvinylpyrrolidone, poly(2-ethyl-2-oxazoline), and polyethylene glycol, which were more effective at increased concentration, molecular weight, or hydrophobicity. Conclusion: Altogether, these findings suggest an interaction between amphiphilic domains of polymers with the cell membrane to help cells maintain viability, possibly by facilitating transmembrane pore closure. In this way, serum components or synthetic polymers can be used to increase intracellular delivery by nanoparticle-mediated photoporation while maintaining high cell viability.


Assuntos
Citoproteção , Sistemas de Liberação de Medicamentos , Espaço Intracelular/química , Luz , Nanopartículas/química , Soro/química , Carboximetilcelulose Sódica/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos da radiação , Citoproteção/efeitos da radiação , Fibroblastos/efeitos da radiação , Humanos , Lasers , Peso Molecular , Poloxâmero/química , Polietilenoglicóis/química , Fuligem/química , Viscosidade
15.
Molecules ; 26(9)2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064423

RESUMO

In the present study, we evaluated for the first time the photoprotective effect of fish bone bioactive peptides (FBBP) preparation isolated from silver carp (Hypophthalmichthys molitrix) discarded tissue using in vitro experimental models of skin cells exposed to ultraviolet B (UVB) irradiation and stressing agents. FBBP preparation was obtained by papain treatment of minced bones and centrifugal ultrafiltration, and the molecular weight (MW) distribution was characterized by size exclusion and reversed-phase high performance liquid chromatography (RP-HPLC). In vitro assessment of the effect of FBBP pretreatment in UVB-irradiated L929 fibroblasts and HaCaT keratinocytes revealed their cytoprotective activity. Their capacity to efficiently reduce reactive oxygen species (ROS) production and lipid peroxidation varied in a dose-dependent manner, and it was greater in fibroblasts. A decrease of proinflammatory cytokines secretion, in particular of tumor necrosis factor alpha (TNF-α), was found after FBBP pretreatment of THP-1-derived inflamed macrophages. Melanin production and tyrosinase activity investigated in UVB-irradiated Mel-Juso cells were lowered in direct relation to FBBP concentrations. FBBP fractions with high radical scavenging activity were separated by ion exchange chromatography, and two collagenic sequences were identified. All these results offer new scientific data on aquaculture fish bone-derived peptides confirming their ability to control the antioxidant, anti-inflammatory and pigmentation processes developed during UV irradiation of skin cells and recommend their use as valuable natural ingredients of photoprotective cosmeceutical products.


Assuntos
Osso e Ossos/efeitos dos fármacos , Inflamação/patologia , Peptídeos/farmacologia , Pigmentação , Pele/efeitos da radiação , Raios Ultravioleta , Animais , Antioxidantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Citoproteção/efeitos dos fármacos , Citoproteção/efeitos da radiação , Peixes , Células HaCaT/efeitos dos fármacos , Células HaCaT/efeitos da radiação , Humanos , Mediadores da Inflamação/metabolismo , Espaço Intracelular/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Malondialdeído/metabolismo , Melaninas/biossíntese , Camundongos , Peso Molecular , Oxirredução/efeitos dos fármacos , Oxirredução/efeitos da radiação , Peptídeos/isolamento & purificação , Pigmentação/efeitos dos fármacos , Pigmentação/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Espectrofotometria Ultravioleta , Células THP-1
16.
Molecules ; 26(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068613

RESUMO

Nowadays, natural dyes are expected by the cosmetic and food industries. In contrast to synthetic dyes, colorants derived from natural sources are more environmentally friendly and safer for human health. In this work, plant extracts from Gomphrena globasa L., Clitoria ternatea L., Carthamus tinctorius L., Punica granatum L. and Papaver rhoeas L. as the natural and functional dyes for the cosmetics industry were assessed. Cytotoxicity on keratinocyte and fibroblast cell lines was determined as well as antioxidant and anti-aging properties by determining their ability to inhibit the activity of collagenase and elastase enzymes. In addition, the composition of the extracts was determined. The obtained extracts were also applied in face cream formulation and color analyses were performed. It has been shown that the obtained extracts were characterized by no cytotoxicity and a high antioxidant potential. The extracts also show strong ability to inhibit the activity of collagenase and moderate ability to inhibit elastase and provide effective and long-lasting hydration after their application on the skin. Application analyses showed that the extracts of P. rhoeas L., C. ternatea L. and C. tinctorius L. can be used as effective cosmetic dyes that allow for attainment of an intense and stable color during the storage of the product. The extracts of P. granatum L. and G. globasa L., despite their beneficial effects as active ingredients, did not work effectively as cosmetic dyes, because cosmetic emulsions with these extracts did not differ significantly in color from emulsions without the extract.


Assuntos
Antioxidantes/farmacologia , Corantes/farmacologia , Cosméticos/farmacologia , Citoproteção , Dessecação , Flores/química , Extratos Vegetais/farmacologia , Benzotiazóis/química , Compostos de Bifenilo/química , Morte Celular/efeitos dos fármacos , Colagenases/metabolismo , Cor , Citoproteção/efeitos dos fármacos , Células HaCaT , Humanos , Cinética , Inibidores de Metaloproteinases de Matriz/farmacologia , Oxazinas/metabolismo , Elastase Pancreática/antagonistas & inibidores , Elastase Pancreática/metabolismo , Picratos/química , Plantas/química , Creme para a Pele/farmacologia , Ácidos Sulfônicos/química , Raios Ultravioleta , Perda Insensível de Água/efeitos dos fármacos , Xantenos/metabolismo
17.
Aging (Albany NY) ; 13(12): 15964-15989, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34031264

RESUMO

A traditional Chinese medicinal fungus, Antrodia salmonea (AS), with antioxidant properties is familiar in Taiwan but anti-cancer activity of AS in human colon cancer is ambiguous. Hence, we explored the anti-cancer activity of AS in colon cancer cells. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that AS showed a remarkable effect on cell viability in colon cancer cells; SW620, HCT116, and HT29. Annexin V/propidium iodide (PI) stained cells indicated that AS induced both early/late apoptosis in SW620 cells. Additionally, cells treated with AS induced caspase-3 activation, poly (ADP-ribose) polymerase (PARP) cleavage, mitochondrial dysfunction, and Bcl-2 associated X (Bax)/B-cell lymphoma (Bcl-2) dysregulation. Microtubule- associated protein 1A/1B-light chain 3B (LC3-II) accumulation, sequestosome 1 (p62/SQSTM1) activation, autophagy related 4B cysteine peptidase (ATG4B) inactivation, acidic vesicular organelles (AVOs) formation, and Beclin-1/Bcl-2 dysregulation revealed that AS-induced autophagy. Interestingly, cells pretreated with 3-methyladenine (3-MA) strengthened AS-induced caspase-3/apoptosis. Suppression of apoptosis by z-Val-Ala-Asp fluoromethyl ketone (Z-VAD-FMK) did not however block AS-induced autophagy, suggesting that autophagy was not attenuated by the AS-induced apoptosis. Application of N-acetylcysteine (NAC) prevented AS-induced cell death, caspase-3 activation, LC3-II accumulation, and AVOs formation, indicating that AS-induced apoptosis and autophagy was mediated by reactive oxygen species (ROS). Furthermore, AS-induced cytoprotective autophagy and apoptosis through extracellular signal-regulated kinase (ERK) signaling cascades. Moreover, in vivo data disclosed that AS inhibited colitis-associated tumorigenesis in azoxymethane (AOM)-dextran sodium sulphate (DSS)-treated mice. For the first time, we report the anti-cancer properties of this potentially advantageous mushroom for the treatment of human colon cancer.


Assuntos
Apoptose , Autofagia , Neoplasias do Colo/patologia , Citoproteção , Polyporales/química , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Azoximetano , Proteína Beclina-1/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cloroquina/farmacologia , Colite/induzido quimicamente , Colite/complicações , Neoplasias do Colo/etiologia , Citoproteção/efeitos dos fármacos , Sulfato de Dextrana , Progressão da Doença , Humanos , Inflamação/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos ICR , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteína X Associada a bcl-2/metabolismo
18.
Chem Biol Interact ; 345: 109534, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34051206

RESUMO

Sepsis triggers liver dysfunction with high morbidity and mortality. Here, we elucidated the effect of anemoside B4 on sepsis in cecal ligation and puncture (CLP)-induced mouse model and LPS-induced primary hepatocytes. Following CLP surgery, septic mice were intraperitoneally injected with anemoside B4 (50 or 100 mg/kg). Anemoside B4 improved septic mouse survival rate, decreased serum AST and ALT levels and attenuated liver histopathologic damages. Western blot analysis showed that anemoside B4 elevated the expression of Beclin-1, LC3II/LC3I, Atg3, Atg5, and Atg7, and reduced p62, suggesting the restoration of autophagy flux in liver. More autophagic vesicles were observed in liver after anemoside B4 treatment using transmission electron microscopy. Using ELISA and commercial enzyme kits, we found that anemoside B4 decreased serum TNF-α, IL-6, and IL-1ß levels and increased CAT, SOD and GSH activities. TUNEL staining and western blot revealed that anemoside B4 suppressed cell apoptosis, along with decreased Bax, leaved caspase-3, cleaved PARP, but increased Bcl-2. Consistent with in vivo findings, anemoside B4 inhibited apoptosis, inflammatory response, and oxidative stress and enhanced autophagy in LPS-induced primary hepatocytes. Importantly, these cellular processes were possibly mediated by mTOR/p70S6K signaling, as reflected by the offset of 3-MA in the immunosuppression of anemoside B4.


Assuntos
Autofagia/efeitos dos fármacos , Fígado/lesões , Fígado/patologia , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Saponinas/farmacologia , Sepse/patologia , Serina-Treonina Quinases TOR/metabolismo , Alanina Transaminase/sangue , Animais , Apoptose/efeitos dos fármacos , Aspartato Aminotransferases/sangue , Citoproteção/efeitos dos fármacos , Interleucina-1beta/sangue , Interleucina-6/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/sangue
19.
Mol Cell ; 81(10): 2201-2215.e9, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34019789

RESUMO

The multi-subunit bacterial RNA polymerase (RNAP) and its associated regulators carry out transcription and integrate myriad regulatory signals. Numerous studies have interrogated RNAP mechanism, and RNAP mutations drive Escherichia coli adaptation to many health- and industry-relevant environments, yet a paucity of systematic analyses hampers our understanding of the fitness trade-offs from altering RNAP function. Here, we conduct a chemical-genetic analysis of a library of RNAP mutants. We discover phenotypes for non-essential insertions, show that clustering mutant phenotypes increases their predictive power for drawing functional inferences, and demonstrate that some RNA polymerase mutants both decrease average cell length and prevent killing by cell-wall targeting antibiotics. Our findings demonstrate that RNAP chemical-genetic interactions provide a general platform for interrogating structure-function relationships in vivo and for identifying physiological trade-offs of mutations, including those relevant for disease and biotechnology. This strategy should have broad utility for illuminating the role of other important protein complexes.


Assuntos
RNA Polimerases Dirigidas por DNA/química , RNA Polimerases Dirigidas por DNA/genética , Mutação/genética , Andinocilina/farmacologia , Proteínas de Bactérias/metabolismo , Morte Celular/efeitos dos fármacos , Cromossomos Bacterianos/genética , Citoproteção/efeitos dos fármacos , Proteínas do Citoesqueleto/metabolismo , Escherichia coli/genética , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Mutagênese Insercional/genética , Peptídeos/metabolismo , Fenótipo , Relação Estrutura-Atividade , Transcrição Genética , Uridina Difosfato Glucose/metabolismo
20.
J Neuroimmunol ; 355: 577567, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33887539

RESUMO

There is growing evidence that fine particulate matter (PM2.5) is a considerable risk factor for neurodegenerative diseases. Scorpion venom heat-resistant synthetic peptide (SVHRSP) plays a neuroprotective effect by promoting neurogenesis and neuron axon growth. In this study, SVHRSP inhibited the level of TLR4, autophagy and PM2.5-induced microglia M1 polarization, thereby promoting Phosphorylation of PI3K and AKT, inhibiting the expression of NF-κB. Moreover, SVHRSP suppressed the cytotoxic factors and increased the cytoprotective factor. This research demonstrates that SVHRSP relieves PM2.5-induced microglial polarization via TLR4-mediated autophagy activating PI3K/AKT/NF-κB signaling pathway, which provides new insights for the treatment of PM2.5-induced neurodegenerative diseases.


Assuntos
Microglia/metabolismo , NF-kappa B/metabolismo , Material Particulado/toxicidade , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Venenos de Escorpião/farmacologia , Animais , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Linhagem Celular , Polaridade Celular/efeitos dos fármacos , Polaridade Celular/fisiologia , Citoproteção/efeitos dos fármacos , Citoproteção/fisiologia , Camundongos , Microglia/efeitos dos fármacos
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