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1.
J Ethnopharmacol ; 247: 112299, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31606537

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Hua-Feng-Dan (HFD) is a traditional Chinese medicine used for neurological disorders. HFD contains cinnabar (HgS) and realgar (As4S4). The ethnopharmacological basis of cinnabar and realgar in HFD is not known. AIM OF THE STUDY: To address the role of cinnabar and realgar in HFD-produced neuroprotection against neurodegenerative diseases and disturbance of gut microbiota. MATERIALS AND METHODS: Lipopolysaccharide (LPS) plus rotenone (ROT)-elicited rat dopaminergic (DA) neuronal damage loss was performed as a Parkinson's disease animal model. Rats were given a single injection of LPS. Four months later, rats were challenged with the threshold dose of ROT. The clinical dose of HFD was administered via feed, starting from ROT administration for 46 days. Behavioral dysfunction was detected by rotarod and Y-maze tests. DA neuron loss and microglial activation were assessed via immunohistochemical staining and western bolt analysis. The colon content was collected to extract bacterial DNA followed by real-time PCR analysis with 16S rRNA primers. RESULTS: LPS plus ROT induced neurotoxicity, as evidenced by DA neuron loss in substantia nigra, impaired behavioral functions and increased microglial activation. HFD-original (containing 10% cinnabar and 10% realgar) rescued loss of DA neurons, improved behavioral dysfunction and attenuated microglial activation. Compared with HFD-original, HFD-reduced (3% cinnabar and 3% realgar) was also effective, but to be a less extent, while HFD-removed (without cinnabar and realgar) was ineffective. In analysis of gut microbiome, the increased Verrucomicrobiaceae and Lactobacteriaceae, and the decreased Enterobacteeriaceae by LPS plus ROT were ameliorated by HFD-original, and to be the less extent by HFD-reduced. CONCLUSION: Cinnabar and realgar are active ingredients in HFD to exert beneficial effects in a neurodegenerative model and gut microbiota.


Assuntos
Arsenicais/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Compostos de Mercúrio/farmacologia , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/tratamento farmacológico , Sulfetos/farmacologia , Animais , Arsenicais/química , Arsenicais/uso terapêutico , DNA Bacteriano/isolamento & purificação , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/genética , Enterobacteriaceae/isolamento & purificação , Etnofarmacologia , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/imunologia , Humanos , Mediadores da Inflamação/metabolismo , Lactobacillaceae/efeitos dos fármacos , Lactobacillaceae/genética , Lactobacillaceae/isolamento & purificação , Lipopolissacarídeos/toxicidade , Masculino , Compostos de Mercúrio/química , Compostos de Mercúrio/uso terapêutico , Microglia/efeitos dos fármacos , Microglia/imunologia , Microglia/patologia , Degeneração Neural , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/imunologia , Síndromes Neurotóxicas/patologia , RNA Ribossômico 16S/genética , Ratos , Rotenona/toxicidade , Sulfetos/química , Sulfetos/uso terapêutico , Verrucomicrobia/efeitos dos fármacos , Verrucomicrobia/genética , Verrucomicrobia/isolamento & purificação
2.
Chem Commun (Camb) ; 55(87): 13148-13151, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31617549

RESUMO

Cu2ZnSnS4 nanocrystals (CZTS NCs) have been demonstrated to be effective in tumor therapy as a novel susceptible agent for microwave thermal and microwave dynamic therapy. CZTS NCs intensify the heating effect of microwaves with a significant temperature increase of about 15 °C compared to the control group and showed remarkable anti-tumor performance after 5 min of microwave irradiation. For the first time, we report the microwave absorption performance and singlet oxygen production of CZTS NCs used in microwave therapy, which reveals new opportunities for novel combined mechanisms of microwave thermal and microwave dynamic tumor therapies.


Assuntos
Antineoplásicos/uso terapêutico , Cobre/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Micro-Ondas , Nanopartículas/uso terapêutico , Sulfetos/uso terapêutico , Temperatura Ambiente , Estanho/uso terapêutico , Zinco/uso terapêutico , Animais , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Terapia Combinada , Cobre/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Nanopartículas/química , Tamanho da Partícula , Relação Estrutura-Atividade , Sulfetos/química , Propriedades de Superfície , Estanho/química , Zinco/química
3.
J Pharmacol Sci ; 140(2): 162-170, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31285125

RESUMO

QTc prolongation has been observed during arsenic trioxide and realgar's clinical use, and become a huge obstacle for the application. Our lab has obtained the soluble arsenic from realgar named realgar transforming solution or RTS. In this study, we first evaluated the cytotoxicity on NB4 cell and found that RTS could remarkably inhibit proliferation of NB4 than arsenic trioxide. Then we figured out the QTc prolongation of RTS treatment contrasted with arsenic trioxide; results revealed that arsenic trioxide prolonged corrected QTc of mice by 20.1% and showed 1.9-fold higher cytotoxicity on H9c2 cell than RTS. On the contrary, there could not find any QTc prolongation of mice in RTS treatment. Also, arsenic trioxide elevated the intercellular calcium accumulation of H9c2 cell by 2.02-fold v.s control and RTS. HE staining and Masson's trichrome staining had shown that there was no injured section after RTS treatments. IK1 currents of rat ventricular cardiomyocytes were diminished by 45.0% after treating with arsenic trioxide while RTS showed no significance than the control group. The results above indicated that RTS could serve as an alternative arsenic agent on leukemia and had a lower risk of cardiotoxicity.


Assuntos
Arsenicais , Cardiotoxicidade/etiologia , Sulfetos/toxicidade , Animais , Arsenicais/efeitos adversos , Arsenicais/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Humanos , Leucemia/tratamento farmacológico , Síndrome do QT Longo/induzido quimicamente , Masculino , Camundongos , Ratos Wistar , Risco , Soluções , Sulfetos/efeitos adversos , Sulfetos/uso terapêutico
4.
Mol Cell Biochem ; 460(1-2): 151-164, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31280436

RESUMO

Diallyl trisulfide (DATS) is distinguished as the most potent polysulfide isolated from garlic. The aim of our study was to investigate effects of oral administration of DATS on healthy and diabetic rats, with special attention on heart function. Rats were randomly divided into four groups: CTRL (healthy rats), DATS (healthy rats treated with DATS), DM (diabetic rats), DM + DATS (diabetic rats treated with DATS). DATS (40 mg/kg of body weight) was administered every other day for 3 weeks, at the end of which rats underwent echocardiography, glycemic measurement and redox status assessment. Isolated rat hearts were subjected to 30 min global ischemia and 60 min reperfusion, after which heart tissue was counterstain with hematoxylin and eosin and cardiac Troponin T staining (cTnT), while expression of Bax, B cell lymphoma 2 (Bcl-2), caspase-3, caspase-9 and superoxide dismutase-2 were examined in the left ventricle. DATS treatment significantly reduced blood glucose levels of diabetic rats, and improved cardiac function recovery, diminished oxidation status, attenuated cardiac remodeling and inhibited myocardial apoptosis in healthy and diabetic rats. DATS treatment causes promising cardioprotective effects on ex vivo-induced ischemia/reperfusion (I/R) injury in diabetic and healthy rat heart probably mediated by inhibited myocardial apoptosis. Moreover, appropriate DATS consumption may provide potential co-therapy or prevention of hyperglycemia and various cardiac complications in rats with DM.


Assuntos
Compostos Alílicos/uso terapêutico , Cardiotônicos/uso terapêutico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/tratamento farmacológico , Sulfetos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Cardiotônicos/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Masculino , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Traumatismo por Reperfusão/fisiopatologia
5.
Iran J Immunol ; 16(2): 170-181, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31182691

RESUMO

BACKGROUND: Realgar, an arsenic tetrasulfide compound, is a highly recognized traditional Chinese medicinal prescription that has been widely used to treat various diseases such as inflammatory diseases. However, there are still some problems in the clinical treatment of Realgar, such as large oral dose and high potential toxicity. OBJECTIVE: To evaluate effects of Realgar nanoparticles on lupus nephritis (LN) in vivo in MRL/lpr mice. METHODS: Ten-week mice were orally administered every day for eight consecutive weeks except the mice of normal model groups. The serum levels of anti-ds-DNA antibody IgG, IgM, IFN-γ, Creatinine (Cr), and blood urea nitrogen (BUN) were determined, and 24-hour urine protein was also measured. Renal inflammatory pathology analysis was assessed by hematoxylin-eosin (H&E) staining. The expression of phosphorylated signal transducer and activator of transcription 1 (p-STAT 1) and Janus Kinase 1 (JAK 1) in kidney tissue was determined by direct reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC). RESULTS: The mice treated with Realgar nanoparticle in the high dose-treated (Realgar HD, 0.03 g/kg/d) group exhibited significantly reduced serum levels of anti-dsDNA (p<0.01), IgG (p<0.01), IgM (p<0.01), BUN (p<0.01), Cr (p<0.01), and inflammatory cytokine IFN-γ (p<0.01) as well as proteinuria (p<0.01) compared to the untreated model MRL/lpr mice. Additionally, high doses of Realgar nanoparticles significantly suppressed the phosphorylations of STAT 1(p<0.01) and the renal pathological changes. CONCLUSIONS: The study indicates that Realgar nanoparticles may be a potential agent to treat LN, and the down-regulated p-STAT1 expression suggests that it may be one of the LN treatment targets for Realgar nanoparticles.


Assuntos
Arsenicais/uso terapêutico , Rim/patologia , Nefrite Lúpica/terapia , Nanopartículas/uso terapêutico , Fator de Transcrição STAT1/metabolismo , Sulfetos/uso terapêutico , Animais , Arsenicais/química , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Janus Quinase 1/metabolismo , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Nanopartículas/química , Transdução de Sinais , Sulfetos/química
6.
Eur J Clin Pharmacol ; 75(10): 1355-1360, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31243478

RESUMO

OBJECTIVE: Renal insufficiency may influence the pharmacokinetics of drugs. We have investigated the pharmacokinetic parameters of imrecoxib and its two main metabolites in individuals with osteoarthritis (OA) with normal renal function and renal insufficiency, respectively. METHODS: This was a prospective, parallel, open, matched-group study in which 24 subjects were enrolled (renal insufficiency group, n = 12; healthy control group, n = 12). Blood samples of subjects administered 100 mg imrecoxib were collected at different time points and analyzed. Plasma concentrations of imrecoxib and its two metabolites (M1 and M2) were determined by the liquid chromatography-tandem mass spectrometry method, and pharmacokinetic parameters (clearance [CL], apparent volume of distribution [Vd], maximum (or peak) serum concentration [Cmax], amount of time drug is present in serum at Cmax [Tmax], area under the curve [AUC; total drug exposure across time], mean residence time [MRT] and elimination half-life [t1/2]) were calculated. RESULTS: The demographic characteristics of the two groups were not significantly different, with the exception of renal function. The mean Cmax and AUC0-t (AUC from time 0 to the last measurable concentration) of imrecoxib in the renal insufficiency group were 59 and 70%, respectively, of those of the healthy control volunteers with normal renal function, indicating a significant decline in the former group (P < 0. 05). The mean pharmacokinetic parameters of Ml in the renal insufficiency and healthy control groups did not significantly differ. In contrast, the mean Cmax and AUC0-t of M2 in the renal insufficiency group were 233 and 367%, respectively, of those of the normal renal function group, indicating a significant increase in the former group (P < 0.05). The mean CL/F (clearance/bioavailability) of M2 of the renal insufficiency group was 37% of that of the normal renal function group, indicating a notable reduction in the former group (P < 0.05). CONCLUSION: The exposure of imrecoxib in OA patients with renal insufficiency showed a decline compared to that in healthy subjects. However, in patients with renal insufficiency the exposure of M2 was markedly increased and the CL was noticeably reduced. These results indicate that the dosage of imrecoxib should be reduced appropriately in patients with renal insufficiency.


Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacocinética , Pirróis/farmacocinética , Insuficiência Renal/metabolismo , Sulfetos/farmacocinética , Adulto , Idoso , Inibidores de Ciclo-Oxigenase 2/sangue , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Interações de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Pirróis/sangue , Pirróis/uso terapêutico , Insuficiência Renal/tratamento farmacológico , Sulfetos/sangue , Sulfetos/uso terapêutico
7.
Eur J Med Chem ; 176: 195-207, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31103900

RESUMO

Previously, we focused on a series of 2-aminobenzamide-based histone deacetylase (HDAC) inhibitors, compound 9 of which displayed potent HDAC inhibitory activity against HDAC1 and HDAC2, and moderate anti-proliferative activity against several cancer cell lines. In the current study, we have designed and synthesized a series of novel HDAC inhibitors based on thioether moiety with 9 as a lead compound. Representative compounds12 g and 12 h showed apparently potent anti-proliferative activities against five solid cancer cell lines: A549, HCT116, Hela, A375 and SMMC7721, and low cytotoxicity against NIH 3T3 normal cells. Especially, 12 g and 12 h also revealed potent HDAC inhibitory activity against HDAC1, 2 and 3. In addition, the two compounds could arrest cell cycle in G2/M phase and promote cell apoptosis. Moreover, they showed extended inhibition of colony formation and effectively blocked cell migration towards A549 cancer cells. Furthermore, 12 g and 12 h possessed better pharmacokinetic properties than the lead compound 9. Benefiting from these results, we also explored 12 g and 12 h in the A549 xenografts model for in vivo antitumor activity. The in vivo experiment indicated that 12 g and 12 h could evidently augment antitumor activity (TGI = 56.9% and 62.7% respectively).


Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Sulfetos/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Benzamidas/síntese química , Benzamidas/farmacocinética , Benzamidas/toxicidade , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacocinética , Inibidores de Histona Desacetilases/toxicidade , Humanos , Camundongos , Simulação de Acoplamento Molecular , Células NIH 3T3 , Sulfetos/síntese química , Sulfetos/farmacocinética , Sulfetos/toxicidade , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Toxicol Mech Methods ; 29(6): 438-444, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30822191

RESUMO

Formulation optimization and antidotal combination therapy are the two important tools to enhance the antidotal protection of the cyanide (CN) antidote dimethyl trisulfide (DMTS). The focus of this study is to demonstrate how the formulation with polysorbate 80 (Poly80), an excipient used in pharmaceutical technology, and the combinations with other CN antidotes having different mechanisms of action enhance the antidotal efficacy of the unformulated (neat) DMTS. The LD50 for CN was determined by the statistical Dixon up-and-down method on mice. Antidotal efficacy was expressed as antidotal potency ratio (APR). CN was injected subcutaneously one minute prior to the antidotes' injection intramuscularly. The APR values of 1.17 (dose: 25 mg/kg bodyweight) and 1.45 (dose: 50 mg/kg bodyweight) of the neat DMTS were significantly enhanced by the Poly80 formulation at both investigated doses to 2.03 and 2.33, respectively. The combination partners for the Poly80 formulated DMTS (DMTS-Poly80; 25 and 50 mg/kg bodyweight) were 4-nitrocobinamide (4NCbi) (20 mg/kg bodyweight) and aquohydroxocobinamide (AHCbi; 50, 100, and 250 mg/kg bodyweight). When DMTS-Poly80 (25 and 50 mg/kg bodyweight; APR = 2.03 and 2.33, respectively) was combined with 4NCbi (20 mg/kg bodyweight; APR = 1.35), significant increase in the APR values were noted at both DMTS doses (APR = 2.38 and 3.12, respectively). AHCbi enhanced the APR of DMTS-Poly80 (100 mg/kg bodyweight; APR = 3.29) significantly only at the dose of 250 mg/kg bodyweight (APR = 5.86). These studies provided evidence for the importance of the formulation with Poly80 and the combinations with cobinamide derivatives with different mechanisms of action for DMTS as a CN antidote candidate.


Assuntos
Antídotos/uso terapêutico , Cobamidas/uso terapêutico , Cianeto de Potássio/envenenamento , Sulfetos/uso terapêutico , Animais , Antídotos/administração & dosagem , Antídotos/química , Cobamidas/administração & dosagem , Cobamidas/química , Relação Dose-Resposta a Droga , Composição de Medicamentos , Quimioterapia Combinada , Excipientes , Dose Letal Mediana , Masculino , Camundongos Endogâmicos , Polissorbatos , Sulfetos/administração & dosagem , Sulfetos/química
9.
Int J Pharm ; 562: 135-150, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30904728

RESUMO

Copper sulfide nanoparticles (CuS NPs), emerging nanoplatforms with dual diagnostic and therapeutic applications, are being actively investigated in this era of "war on cancer" owing to their versatility and adaptability. This article discusses the pros and cons of using CuS NPs in diagnostics, therapeutics, and theranostics. The first section introduces CuS NPs and discusses the features that render them more advantageous than other established nanoplatforms in cancer management. Subsequent sections include specific in vitro and in vivo results of different studies showing the potential of CuS NPs as nanoplatforms. Methods used for visualization (photoacoustic imaging and magnetic resonance imaging) of CuS NPs and treatment (phototherapy and combinatorial therapy) have also been discussed. Furthermore, the challenges and opportunities associated with using CuS NPs have been elucidated. Further investigations on CuS NPs are required to translate it for clinical applications.


Assuntos
Cobre/uso terapêutico , Nanopartículas/uso terapêutico , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Sulfetos/uso terapêutico , Animais , Humanos , Nanomedicina Teranóstica
10.
Int Immunopharmacol ; 71: 132-138, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30897500

RESUMO

BACKGROUND: Diallyl Trisulfide (DATS) is an organosulfur compound extracted from garlic bulb, and exerts cardioprotective, anti-inflammatory, antioxidant, antimicrobial and anticancer effects. But its role in the pathogenesis of rheumatoid arthritis (RA) is unknown. Here we explored the influence of DATS on human fibroblast-like synoviocytes (FLS) isolated from RA patients and a mouse model of collagen-induced arthritis (CIA) and the underlying mechanism. METHODS: RA-FLS were cultured and treated with different concentrations of DATS. The CCK8 assay was used to assess cell proliferation while cell apoptosis was detected by flow cytometry and western blot. The IL-8, IL-6 and IL-1ß levels were determined using RT-qPCR and ELISA assay. The expression of proteins of the NF-κB and Wnt pathways were measured using western blot. Furthermore, the effect of DATS was also explored in vivo using the collagen-induced arthritis mouse model. The Th17/Treg pattern obtain from cells of spleen of collagen-induced arthritis mouse model was detected by flow cytometry. RESULTS: Our results showed that DATS could decrease cell viability and introduce apoptosis in RA-FLS. Furthermore, DATS significantly attenuated the production of key inflammatory cytokines induced by RA-FLS cells following treatment with tumor necrosis α (TNF-α) at a concentration of 100 µM or higher. This was due to its inhibitory effect on the NF-κB and Wnt pathway signaling in RA-FLS. Additionally, DATS decreased the production of inflammatory cytokines and regulated the immune function by restoring the balance between Th17 and Treg in CIA mouse model. CONCLUSIONS: In conclusion, DATS may serve as a potential curative agent for RA.


Assuntos
Compostos Alílicos/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Fibroblastos/fisiologia , Sulfetos/uso terapêutico , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Idoso , Animais , Apoptose , Células Cultivadas , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos DBA , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Transdução de Sinais , Membrana Sinovial/patologia , Proteínas Wnt/metabolismo
11.
Int J Nanomedicine ; 14: 875-888, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30787606

RESUMO

Background: Hydrogen sulfide (H2S) has shown promising therapeutic benefits in reversing a variety of pathophysiological processes in cardiovascular system, including myocardial ischemia-reperfusion (IR) injury. However, the achievement of controlled and sustained release of H2S has been a technical bottleneck that limits the clinical application of the gas molecule. Methods: The current study describes the development of mesoporous iron oxide nanoparticles (MIONs) which were loaded with diallyl trisulfide (DATS), a H2S donor compound, and calibrated by stimulated Raman scattering/transient absorption. Results: The synthesized MIONs were characterized with excellent mesoporosity and a narrow size distribution, which enabled them to slow down the release of H2S to a suitable rate and prolong the plateau period. The controlled-release feature of DATS-MIONs resulted in little adverse effect both in vitro and in vivo, and their protective effect on the heart tissue that underwent IR injury was observed in the mouse model of myocardial ischemia. The rapid biodegradation of DATS-MIONs was induced by Kupffer cells, which were specialized macrophages located in the liver and caused limited hepatic metabolic burden. Conclusion: The sustained-release pattern and excellent biocompatibility make DATS-MIONs a promising H2S donor for research and medical purposes.


Assuntos
Compostos Alílicos/uso terapêutico , Cardiotônicos/uso terapêutico , Compostos Férricos/química , Sulfeto de Hidrogênio/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miocárdio/patologia , Nanopartículas/química , Sulfetos/uso terapêutico , Compostos Alílicos/administração & dosagem , Animais , Cardiotônicos/farmacologia , Linhagem Celular , Preparações de Ação Retardada , Coração/efeitos dos fármacos , Homeostase , Masculino , Camundongos , Isquemia Miocárdica , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Nanopartículas/toxicidade , Nanopartículas/ultraestrutura , Sulfetos/administração & dosagem
12.
Andrologia ; 51(5): e13240, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30706510

RESUMO

Men with hypertension often develop erectile dysfunction (ED). The present study aimed to examine the effects of sodium hydrosulphide (NaHS), a hydrogen (H2 S) donor, treatment on ED in nitric oxide synthase (NOS) inhibitor (L-NAME)-induced hypertensive rats. Forty adult Sprague-Dawley rats were divided into four groups: control, NaHS (0.037 mg kg day-1 )-treated control, L-NAME-induced hypertension (40 mg kg day-1 ) and NaHS-treated L-NAME-induced hypertension. The ratio of intracavernosal pressure to mean arterial pressure and isometric tension of corpus cavernosum (CC) were measured. The penile expression of endothelial and neuronal NOS (eNOS and nNOS), inflammation markers [nuclear factor kappa B (NF-κB) and inhibitor kappa B alpha (IκBα)], H2 S-producing enzymes[cystathionine ß-synthase (CBS) and cystathionine γ-lyase (CSE)], the smooth muscle/collagen ratio and H2 S concentrations were determined. The blood pressure was significantly increased in the hypertensive group, but not reversed by NaHS. The erectile response in hypertensive rats was partially prevented by NaHS. The relaxation response to electrical field stimulation was increased in CC from NaHS-treated hypertensive rats. NaHS treatment restored decreased protein expression of eNOS, nNOS and CSE as well as smooth muscle/collagen ratio and H2 S levels and increased NF-κB and IκBα protein expression in the penile tissue of hypertensive rats. NaHS promoted the recovery of erectile responses in hypertensive rats by improvement of neuronal function and downregulation of fibrosis and NF-κB signalling.


Assuntos
Disfunção Erétil/tratamento farmacológico , Hipertensão/complicações , Ereção Peniana/efeitos dos fármacos , Pênis/efeitos dos fármacos , Sulfetos/farmacologia , Animais , Cistationina gama-Liase/metabolismo , Modelos Animais de Doenças , Disfunção Erétil/etiologia , Fibrose/tratamento farmacológico , Fibrose/patologia , Humanos , Sulfeto de Hidrogênio/farmacologia , Hipertensão/induzido quimicamente , Masculino , NG-Nitroarginina Metil Éster/toxicidade , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Pênis/metabolismo , Pênis/patologia , Ratos , Ratos Sprague-Dawley , Sulfetos/uso terapêutico , Resultado do Tratamento
13.
Dermatol Ther ; 32(4): e12849, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30707471

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disease of uncertain etiology that affects multiple tissues and organs. Tetra-arsenic tetra-sulfide (As4 S4 ), a traditional Chinese medicine, is effective on acute promyelocytic leukemia with mild side effects. In our previous study, BXSB lupus-prone mice treated with As4 S4 has showed improved monocytosis, decreased serum interleukin (IL)-6 and suppressed skin, liver and renal lesions with well-tolerance. In this study, we explored the effect and mechanism of As4 S4 on the MRL/lpr mice. MRL/lpr and wild MRL/MpJ mice were divided into control and As4 S4 treatment groups and dosed with As4 S4 or placebo for 8 weeks. We found that As4 S4 prevented the skin, renal and lung lesions of MRL/lpr mice. As4 S4 significantly decreased the double negative T (DN T) cells and reduced the serum levels of IL-17, IL-10, and antinuclear antibodies titer. Further results revealed that the FasL was decreased, and activated caspases elevated in DN T cells in As4 S4 treated MRL/lpr mice. Taken together, As4 S4 could selectively suppresses DN T cells by inducing apoptosis. It also reduced inflammatory cytokines IL-17, which may be produced by DN T cells. As4 S4 may represent a new therapy for SLE.


Assuntos
Arsenicais/uso terapêutico , Interleucina-17/antagonistas & inibidores , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Sulfetos/uso terapêutico , Linfócitos T/efeitos dos fármacos , Animais , Arsenicais/farmacologia , Feminino , Interleucina-10/fisiologia , Interleucina-17/fisiologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/mortalidade , Camundongos , Camundongos Endogâmicos MRL lpr , Tamanho do Órgão/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/patologia , Sulfetos/farmacologia , Linfócitos T/imunologia
14.
Nanomedicine ; 17: 1-12, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30654184

RESUMO

Taking advantage of the mesoporous structure of bismuth sulfide nanostars (Bi2S3 NSs), a chemotherapeutic drug of doxorubicin (DOX) and a photosensitizer of chlorin e6 (Ce6) were concurrently loaded in the PEGylated Bi2S3 NSs to formulate a multifunctional nanocomplex (BPDC NSs) for tumor theranostics. BPDC NSs have excellent photothermal conversion efficiency and a capacity of yielding reactive oxygen species (ROS) upon laser irradiation, and can realize on-demand drug release by either pH-activation or thermal induction. Accumulation of the nanodrug could be monitored in real-time by infrared thermal imaging, fluorescence imaging and computed tomography (CT). More importantly, the combination effects of photothermal therapy (PTT), photodynamic therapy (PDT) and chemotherapy were demonstrated to dramatically suppress solid tumors without recurrence in vivo. Featuring low systemic toxicity and high biocompatibility, this nanoplatform could be a promising derivative of Bi2S3 NSs for imaging-guided theranostics of cancer.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Fármacos Fotossensibilizantes/administração & dosagem , Porfirinas/administração & dosagem , Animais , Antibióticos Antineoplásicos/uso terapêutico , Bismuto/uso terapêutico , Linhagem Celular Tumoral , Preparações de Ação Retardada/uso terapêutico , Doxorrubicina/uso terapêutico , Hipertermia Induzida , Camundongos , Nanopartículas/uso terapêutico , Nanopartículas/ultraestrutura , Imagem Óptica , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Polietilenoglicóis/uso terapêutico , Porosidade , Porfirinas/uso terapêutico , Sulfetos/uso terapêutico , Nanomedicina Teranóstica , Tomografia Computadorizada por Raios X
15.
Int Immunopharmacol ; 69: 79-87, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30682720

RESUMO

Cutaneous toxicities are the commonest side effects in patients with cancer treated using epidermal growth factor receptor inhibitors such as erlotinib. For patients with such toxicities, there is a lack of safe, effective pharmacological agents. Here we established a skin toxicity model and investigated the preventive and therapeutic effect of Diallyl Trisulfide (DATS) in vivo. The mouse skin toxicities model was established through continuous administration of erlotinib for 49 days. Meanwhile, the mice in the experimental group underwent DATS treatment for 49 days. Hematoxylin and eosin (HE) staining and oil red O staining of back and limb skin was performed to determine whether DATS aqueous extract can reverse the skin toxicities caused by erlotinib. Compared with the erlotinib group, the incidence of rash in the DATS group was lower. In addition, in the DATS group, the degree of skin redness and herpes was mild, the body weight was stable, and the activity was favorable. By comparing the HE and oil red O staining results for the mouse skin, the degree of keratin hyperplasia was determined to be lower in the experimental group than in the erlotinib group, and the number of purulent neutrophils decreased. The number of follicles was relatively less. The release of TNF-α, IL-6 and other inflammatory factors was reduced by DATS. Erlotinib hydrochloride can cause severe skin toxicities, and DATS prevents skin toxicities, its mechanism may be related to DATS reduced erlotinib-induced inflammatory injury.


Assuntos
Compostos Alílicos/uso terapêutico , Antineoplásicos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Cloridrato de Erlotinib/efeitos adversos , Exantema/prevenção & controle , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Pele/efeitos dos fármacos , Sulfetos/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Modelos Animais de Doenças , Receptores ErbB , Cloridrato de Erlotinib/uso terapêutico , Exantema/etiologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Inibidores de Proteínas Quinases/uso terapêutico , Pele/patologia
16.
J Surg Res ; 235: 470-478, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30691831

RESUMO

BACKGROUND: Acute kidney injury is the most serious complication of crush syndrome. Hydrogen sulfide (H2S) is an endogenously produced gaseous signaling molecule. It is involved in homeostatic functions, such as blood pressure control, apoptosis, oxidative stress, and inflammation. In this study, effects of H2S on kidney injury were investigated in a rat model of crush syndrome. METHODS: Rats were divided into six groups (n = 8): Sham (steril saline ip), crush (sterile saline ip), crush + NaHS (sodium hydrosulfide, an H2S donor) (100 µmol/kg ip). All these groups were also separated as 3 and 24 h after decompression. Crush injury was induced by 6 h of direct compression to both hindlimbs of anesthetized rats with blocks weighing 3.6 kg each sides, followed by 3 or 24 h of decompression. Kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, tumor-necrotizing factor-α, transforming growth factor-ß, tissue total oxidant status, and total antioxidant status levels were measured in kidney homogenates 3 and 24 h after decompression. Serum creatine kinase, blood urea nitrogen, and creatinine levels were also measured. Apoptosis was assessed by TUNEL method. Bcl-2 was assessed by immunohistochemistry. Glomerular and tubular structures were also examined histopathologically. RESULTS: NaHS reduced kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, tumor-necrotizing factor-α, transforming growth factor-ß, total oxidant status levels, and increased total antioxidant status levels in kidney 3 and 24 h after decompression. Serum urea, creatinine, and creatine kinase levels also reduced with NaHS. NaHS decreased renal damage and apoptosis in crush-related acute kidney injury. CONCLUSIONS: These results suggest that H2S could reduce crush-related acute kidney injury via anti-inflammatory, antioxidant, and antiapoptotic effects.


Assuntos
Lesão Renal Aguda/prevenção & controle , Síndrome de Esmagamento/complicações , Sulfetos/uso terapêutico , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/metabolismo , Proteínas da Fase Aguda/metabolismo , Animais , Moléculas de Adesão Celular/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Testes de Função Renal , Lipocalinas/metabolismo , Masculino , Estresse Oxidativo , Proteínas Proto-Oncogênicas/metabolismo , Ratos Wistar , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
17.
Appl Biochem Biotechnol ; 188(2): 338-356, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30450513

RESUMO

The therapeutic potency of ultrasonic nanoemulsified garlic oil blend using a non-ionic surfactant (Tween 80) was assessed on pre-diabetic Wistar rats with microalbuminuria. The pre-diabetic condition was induced in male albino Wistar rats by supplementing high-fat diet. The prolonged period of the pre-diabetic state caused renal dysfunctioning, which was indicated by microalbuminuria. Treatment of pre-diabetic rats with nanoemulsified garlic oil blend significantly ameliorated the lipid profile (p < 0.001), urinary albumin (p < 0.01), microprotein (p < 0.001), urinary triglycerides (p < 0.01), serum triglycerides (p < 0.01), serum albumin (p < 0.05), and protein levels (p < 0.01) in comparison to treatment of pre-diabetic rats with garlic oil blend or atorvastatin. Similarly, histopathological investigations indicated a remarkable attenuation in the mesangial expansion and proliferation, glomerular and tubular basement membrane thickening, and the tubular lipid deposits on administering nanoemulsified garlic oil blend than garlic oil blend or atorvastatin. Moreover, nanoemulsified garlic oil blend significantly promoted renal podocin gene expression by 3.98-fold (p < 0.001) and attenuated increased urinary podocin level by 2.92-fold (p < 0.01). Thus, our study affirms that the efficacy of garlic oil blend was augmented upon nanoemulsification, which substantially ameliorated the renal abnormalities observed in the pre-diabetic condition than garlic oil blend or atorvastatin.


Assuntos
Compostos Alílicos/uso terapêutico , Diabetes Mellitus Experimental/dietoterapia , Alho , Rim/efeitos dos fármacos , Fitoterapia , Óleos Vegetais/uso terapêutico , Estado Pré-Diabético/dietoterapia , Sulfetos/uso terapêutico , Albuminúria/dietoterapia , Albuminúria/metabolismo , Albuminúria/patologia , Compostos Alílicos/administração & dosagem , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Sistemas de Liberação de Medicamentos , Emulsões , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/urina , Rim/metabolismo , Rim/patologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/urina , Nanotecnologia , Óleos Vegetais/administração & dosagem , Polissorbatos , Estado Pré-Diabético/metabolismo , Estado Pré-Diabético/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Sulfetos/administração & dosagem , Tensoativos , Regulação para Cima/efeitos dos fármacos
18.
Cancer Chemother Pharmacol ; 83(3): 519-530, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30542770

RESUMO

PURPOSE: This study aimed at investigating the anti-tumor effect of arsenic sulfide (As2S2) against liver cancer both in vivo and in vitro and to elucidate its underlying mechanisms. METHODS: Cell viability of the human hepatocellular carcinoma cell lines SMMC-7721, BEL-7402, HepG2 were measured by CCK-8 assay. The effects of As2S2 on cell proliferation and apoptosis of SMMC-7721 cells were investigated using Calcein-AM and PI staining, Hoechst 33258 staining, crystal violet staining, and JC-1 staining. Cell cycle and Annexin V/PI assay were analyzed via flow cytometry. The expression of apoptosis-related proteins, phosphorylation of PI3K and AKT were detected by Western blotting. H22-bearing mice model was established to evaluate the anti-tumor effect of As2S2 in vivo. HE staining, PCNA was observed via immunohistochemistry, and TUNEL assay was used to assess the anti-proliferation and pro-apoptotic effects of As2S2. RESULTS: As2S2 significantly inhibited the growth of human hepatoma cells SMMC-7721, BEL-7402 and HepG2. As2S2 inhibited cell proliferation effectively by inducing G0/G1 cell cycle arrest in SMMC-7721 cells. As2S2 could increase Bax/Bcl-2 ratio, decrease mitochondrial membrane potential, promote the release of cytochrome c, increase the levels of cleaved caspase-3 and PARP, indicating that As2S2 induced apoptosis in SMMC-7721 cells via mitochondrial-mediated apoptosis pathway. Further research showed that As2S2 inhibited the PI3K/AKT signaling pathway leading to apoptotic cell death. In addition, As2S2 significantly inhibited tumor growth in H22-bearing mice and induced apoptosis by deactivating PI3K/AKT pathway, which was consistent with the in vitro results. CONCLUSION: These findings suggested that As2S2 could induce apoptosis of liver cancer cells in vitro and in vivo, which was related to PI3K/AKT-mediated mitochondrial pathway and may provide a novel promising therapeutic agent for liver cancer treatment.


Assuntos
Apoptose/efeitos dos fármacos , Arsenicais/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Sulfetos/farmacologia , Animais , Arsenicais/uso terapêutico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral/transplante , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Organismos Livres de Patógenos Específicos , Sulfetos/uso terapêutico
19.
Toxicol Mech Methods ; 29(3): 165-176, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30318971

RESUMO

Diabetes is a major noncommunicable life-threatening chronic and pervasive condition that is consuming the world health in a petrifying rate. The circulatory system is one of the major sources of hyperglycemia-induced ROS generation. Historically, garlic has been revered as part of a healthful diet. Organosulfur compounds have been attributed to the medicinal properties and health benefits of garlic. The present study focuses on the ameliorative role of allyl methyl sulfide (AMS) in combating diabetic complications in diabetic rats. Male Wistar rats were randomly divided into four groups. Experimental diabetes was induced by a single intraperitoneal injection (i.p), of streptozotocin (STZ) (40 mg/kg b.w). STZ treated diabetic rats showed significant augment in plasma glucose level, lipidperoxidative (LPO) markers, glycoprotein components (hexose, hexosamine, sialic acid, and fucose), and significant decline in plasma insulin level, nonenzymatic antioxidants and activities of antioxidant enzymes in the circulatory system and tissues. Further, periodic acid-Schiff (PAS) staining of hepatic and renal tissues revealed positive stain accumulation and Western blot investigation of glucose transporter 2 (GLUT 2) in pancreas of STZ-induced hyperglycemic rats. Dietary intervention with AMS (100 mg/kg b.w) for 30 days demonstrated significant protective effects on all the biochemical parameters studied. Besides, biochemical findings were corroborated by histological exertion and Western blot study. The findings of current investigations recommended that AMS can ameliorate the consequences of diabetes due to their antioxidant efficacy and can be used as a potential therapeutic approach. Further studies are warranted to explore the clinical application of AMS.


Assuntos
Compostos Alílicos/uso terapêutico , Antioxidantes/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Alho/química , Glicoproteínas/metabolismo , Hipoglicemiantes/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Sulfetos/uso terapêutico , Compostos Alílicos/isolamento & purificação , Animais , Glicemia/análise , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/enzimologia , Hipoglicemiantes/isolamento & purificação , Insulina/sangue , Masculino , Ratos Wistar , Sulfetos/isolamento & purificação
20.
Oxid Med Cell Longev ; 2018: 2746873, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30581528

RESUMO

Maternal high levels of the redox active amino acid homocysteine-called hyperhomocysteinemia (hHCY)-can affect the health state of the progeny. The effects of hydrogen sulfide (H2S) treatment on rats with maternal hHCY remain unknown. In the present study, we characterized the physical development, reflex ontogeny, locomotion and exploratory activity, muscle strength, motor coordination, and brain redox state of pups with maternal hHCY and tested potential beneficial action of the H2S donor-sodium hydrosulfide (NaHS)-on these parameters. Our results indicate a significant decrease in litter size and body weight of pups from dams fed with methionine-rich diet. In hHCY pups, a delay in the formation of sensory-motor reflexes was observed. Locomotor activity tested in the open field by head rearings, crossed squares, and rearings of hHCY pups at all studied ages (P8, P16, and P26) was diminished. Exploratory activity was decreased, and emotionality was higher in rats with hHCY. Prenatal hHCY resulted in reduced muscle strength and motor coordination assessed by the paw grip endurance test and rotarod test. Remarkably, administration of NaHS to pregnant rats with hHCY prevented the observed deleterious effects of high homocysteine on fetus development. In rats with prenatal hHCY, the endogenous generation of H2S brain tissues was lower compared to control and NaHS administration restored the H2S level to control values. Moreover, using redox signaling assays, we found an increased level of malondialdehyde (MDA), the end product of lipid peroxidation, and decreased activity of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the brain tissues of rats of the hHCY group. Notably, NaHS treatment restored the level of MDA and the activity of SOD and GPx. Our data suggest that H2S has neuroprotective/antioxidant effects against homocysteine-induced neurotoxicity providing a potential strategy for the prevention of developmental impairments in newborns.


Assuntos
Sulfeto de Hidrogênio/metabolismo , Hiper-Homocisteinemia/tratamento farmacológico , Hiper-Homocisteinemia/metabolismo , Animais , Antioxidantes/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Feminino , Glutationa Peroxidase/metabolismo , Homocisteína/sangue , Hiper-Homocisteinemia/sangue , Peroxidação de Lipídeos/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Malondialdeído/sangue , Gravidez , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfetos/uso terapêutico , Superóxido Dismutase/metabolismo
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