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1.
Int J Mol Sci ; 25(7)2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38612589

RESUMO

Lung cancer is the leading cause of cancer death worldwide. Polycyclic aromatic hydrocarbons (PAHs) are metabolized by the cytochrome P450 (CYP)1A and 1B1 to DNA-reactive metabolites, which could lead to mutations in critical genes, eventually resulting in cancer. Omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are beneficial against cancers. In this investigation, we elucidated the mechanisms by which omega-3 fatty acids EPA and DHA will attenuate PAH-DNA adducts and lung carcinogenesis and tumorigenesis mediated by the PAHs BP and MC. Adult wild-type (WT) (A/J) mice, Cyp1a1-null, Cyp1a2-null, or Cyp1b1-null mice were exposed to PAHs benzo[a]pyrene (BP) or 3-methylcholanthrene (MC), and the effects of omega-3 fatty acid on PAH-mediated lung carcinogenesis and tumorigenesis were studied. The major findings were as follows: (i) omega-3 fatty acids significantly decreased PAH-DNA adducts in the lungs of each of the genotypes studied; (ii) decreases in PAH-DNA adduct levels by EPA/DHA was in part due to inhibition of CYP1B1; (iii) inhibition of soluble epoxide hydrolase (sEH) enhanced the EPA/DHA-mediated prevention of pulmonary carcinogenesis; and (iv) EPA/DHA attenuated PAH-mediated carcinogenesis in part by epigenetic mechanisms. Taken together, our results suggest that omega-3 fatty acids have the potential to be developed as cancer chemo-preventive agents in people.


Assuntos
Ácidos Graxos Ômega-3 , Hidrocarbonetos Policíclicos Aromáticos , Humanos , Adulto , Camundongos , Animais , Ácidos Graxos Ômega-3/farmacologia , Adutos de DNA , Carcinogênese , Transformação Celular Neoplásica , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia
2.
Oxid Med Cell Longev ; 2021: 5544600, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34691356

RESUMO

Supplemental oxygen administration is frequently used in premature infants and adults with pulmonary insufficiency. NADPH quinone oxidoreductase (NQO1) protects cells from oxidative injury by decreasing reactive oxygen species (ROS). In this investigation, we tested the hypothesis that overexpression of NQO1 in BEAS-2B cells will mitigate cell injury and oxidative DNA damage caused by hyperoxia and that A-1221C single nucleotide polymorphism (SNP) in the NQO1 promoter would display altered susceptibility to hyperoxia-mediated toxicity. Using stable transfected BEAS-2B cells, we demonstrated that hyperoxia decreased cell viability in control cells (Ctr), but this effect was differentially mitigated in cells overexpressing NQO1 under the regulation of the CMV viral promoter, the wild-type NQO1 promoter (NQO1-NQO1), or the NQO1 promoter carrying the SNP. Interestingly, hyperoxia decreased the formation of bulky oxidative DNA adducts or 8-hydroxy-2'-deoxyguanosine (8-OHdG) in Ctr cells. qPCR studies showed that mRNA levels of CYP1A1 and NQO1 were inversely related to DNA adduct formation, suggesting the protective role of these enzymes against oxidative DNA injury. In SiRNA experiments entailing the NQO1-NQO1 promoter, hyperoxia caused decreased cell viability, and this effect was potentiated in cells treated with CYP1A1 siRNA. We also found that hyperoxia caused a marked induction of DNA repair genes DDB2 and XPC in Ctr cells, supporting the idea that hyperoxia in part caused attenuation of bulky oxidative DNA lesions by enhancing nucleotide excision repair (NER) pathways. In summary, our data support a protective role for human NQO1 against oxygen-mediated toxicity and oxidative DNA lesions in human pulmonary cells, and protection against toxicity was partially lost in SNP cells. Moreover, we also demonstrate a novel protective role for CYP1A1 in the attenuation of oxidative cells and DNA injury. Future studies on the mechanisms of attenuation of oxidative injury by NQO1 should help in developing novel approaches for the prevention/treatment of ARDS in humans.


Assuntos
Pulmão/metabolismo , Pulmão/fisiopatologia , NAD(P)H Desidrogenase (Quinona)/metabolismo , Estresse Oxidativo , Humanos , Pulmão/patologia
3.
Neurotherapeutics ; 18(4): 2651-2663, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34431029

RESUMO

Depression is a common psychiatric illness affecting over 300 million people globally. Acupuncture has been reported to be a safe complementary treatment for depression. This study is aimed to investigate the efficacy and mechanism of combining acupuncture with antidepressants in treating depression compared to the sole use of antidepressants. Seventy depression patients were randomly assigned to the treatment group (n = 50) and control group (n = 20). The treatment group received acupuncture combined antidepressants treatment for 3 weeks, while the control group took antidepressants monotherapy for 3 weeks. Among the 70 patients, 40 participants (20 control; 20 treatment) were randomized for studying functional connectivity (FC) of the dorsolateral prefrontal cortex (DLPFC) measured by the functional near-infrared spectroscopy. The primary outcome was HAMD-17 and secondary outcomes were PHQ-9, and the relationships of resting-state FC (rsFC) with the depression severity. PHQ-9 and HAMD-17 scores in the treatment group were significantly lower than those in the control group at Week 3 (p = 0.01) with effect sizes of -0.4 and -0.61 respectively. The rsFC in F1, F3, AF3, AF7, FC3, FC5 (left DLPFC, 10-20 system), AF8, and F6 (right DLPFC) in the treatment group had significant temporal correlation (p < 0.05, FDR corrected) in DLPFC compared to the channels in the control group. No significant correlation was found between the changes of rsFC and depression severity. In conclusion, depressed patients receiving acupuncture combined with antidepressants have improvement of depressive symptoms and the stronger rsFC in the DLPFC compared to those using antidepressants alone.


Assuntos
Terapia por Acupuntura , Espectroscopia de Luz Próxima ao Infravermelho , Antidepressivos/uso terapêutico , Terapia Combinada , Humanos , Imageamento por Ressonância Magnética
4.
Pharmacology ; 105(7-8): 461-470, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31995806

RESUMO

BACKGROUND/AIMS: We aimed to explore whether ganoderma lucidum polysaccharide (GLP) exhibits antitumor effect on cervical cancer cells. METHODS AND RESULTS: Different concentration of GLP was used to treat cervical cell. The data from cell counting kit-8 assay proved that the optimal working concentration and time of GLP were 200 µg/mL and treated for 48 h. The transwell assay demonstrated that GLP could attenuate the invasion and migration abilities of cervical cancer cells. Moreover, flow cytometry illustrated that GLP could promote the apoptosis of cervical cancer cells and limit the cycle of cervical cancer cells. Western blot assay discovered that the expression of proapoptosis proteins including Bax, Cleaved Caspases 3 and 9 increased and the antiapoptosis protein Bcl-2 decreased after treated with GLP. Moreover, we found that the expression of E-cadherin was increased, and N-cadherin, Vimentin, and Slug were decreased. Meanwhile, the expression of phosphorylated-JAK and phosphorylated-STAT5 was also decreased in cervical cancer cells treated by GLP, suggesting the inhibitory effect on JAK/STAT5 pathways. CONCLUSIONS: All of these data illustrated that GLP could alleviate the activity and aggressiveness, block the cell cycle, and promote the apoptosis of cervical cancer cells, which were possible via inhibiting epithelial-mesenchymal and JAK/STAT5 pathways.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Polissacarídeos Fúngicos/farmacologia , Reishi/química , Transdução de Sinais/efeitos dos fármacos , Neoplasias do Colo do Útero/patologia , Animais , Apoptose , Caderinas/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Gastrópodes/metabolismo , Humanos , Janus Quinases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Transcrição STAT5/metabolismo , Neoplasias do Colo do Útero/metabolismo , Vimentina/metabolismo
5.
ACS Appl Mater Interfaces ; 5(8): 3275-80, 2013 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-23544614

RESUMO

Polydiacetylene supramolecules (PDAs) are unique sensing materials. Upon environmental stimulation, blue PDAs can undergo a colorimetric transition from blue to red accompanied by fluorescence enhancement. In this paper, we report a new PDA system polymerized from a mixed liposome comprising 2-(2-(2-hydroxyethoxy)ethoxy)ethyl pentacosa-10,12-diynoate and pentacosa-10,12-diynoic acid at a 3:7 ratio. The PDA system provided new colorimetric and fluorometric assay methods for screening acetylcholinesterase and its inhibitors through three processes. First, myristoylcholine reacted with PDAs, which then underwent colorimetric and fluorometric transition. Second, acetylcholinesterase catalyzed the hydrolysis of myristoylcholine into tetradecanoic acid, which reduced the myristoylcholine concentration and led to faded color and fluorescence. Third and last, acetylcholinesterase inhibitors retarded the activity of acetylcholinesterase, thereby inducing the recovery of color and fluorescence.


Assuntos
Acetilcolinesterase/análise , Inibidores da Colinesterase/análise , Colorimetria/métodos , Fluorometria/métodos , Polímeros/química , Poli-Inos/química , Avaliação Pré-Clínica de Medicamentos , Polímero Poliacetilênico
6.
PLoS One ; 6(10): e26589, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22066002

RESUMO

Many carcinogenic polycyclic aromatic hydrocarbons (PAHs) and their metabolites can bind covalently to DNA. Carcinogen-DNA adducts may lead to mutations in critical genes, eventually leading to cancer. In this study we report that fish oil (FO) blocks the formation of DNA adducts by detoxification of PAHs. B6C3F1 male mice were fed a FO or corn oil (CO) diet for 30 days. The animals were then treated with seven carcinogenic PAHs including benzo(a)pyrene (BaP) with one of two doses via a single intraperitoneal injection. Animals were terminated at 1, 3, or 7 d after treatment. The levels of DNA adducts were analyzed by the (32)P-postlabeling assay. Our results showed that the levels of total hepatic DNA adducts were significantly decreased in FO groups compared to CO groups with an exception of low PAH dose at 3 d (P = 0.067). Total adduct levels in the high dose PAH groups were 41.36±6.48 (Mean±SEM) and 78.72±8.03 in 10(9) nucleotides (P = 0.011), respectively, for the FO and CO groups at 7 d. Animals treated with the low dose (2.5 fold lower) PAHs displayed similar trends. Total adduct levels were 12.21±2.33 in the FO group and 24.07±1.99 in the CO group, P = 0.008. BPDE-dG adduct values at 7 d after treatment of high dose PAHs were 32.34±1.94 (CO group) and 21.82±3.37 (FO group) in 10(9) nucleotides with P value being 0.035. Low dose groups showed similar trends for BPDE-dG adduct in the two diet groups. FO significantly enhanced gene expression of Cyp1a1 in both the high and low dose PAH groups. Gstt1 at low dose of PAHs showed high levels in FO compared to CO groups with P values being 0.014. Histological observations indicated that FO played a hepatoprotective role during the early stages. Our results suggest that FO has a potential to be developed as a cancer chemopreventive agent.


Assuntos
Carcinógenos/metabolismo , Adutos de DNA/metabolismo , Gorduras Insaturadas na Dieta/farmacologia , Óleos de Peixe/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Dieta , Ácidos Graxos/análise , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/patologia , Masculino , Desintoxicação Metabólica Fase I/genética , Desintoxicação Metabólica Fase II/genética , Camundongos
7.
Zhongguo Zhong Xi Yi Jie He Za Zhi ; 27(8): 745-8, 2007 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-17879544

RESUMO

OBJECTIVE: To observe the efficacy and safety of zhongfu hypotension capsule (ZHC) in treating hypertension of yin-deficiency with sthenic-yang syndrome type. METHODS: Adopting the stratified, block randomized, double-blinded, double-dummy, positive parallel controlled, multi-centered clinical trial method, the tested group was treated by orally taken 3 capsules of ZHC (0.5 g/capsule) twice a day, and the control group was treated by orally taken Lotensin Tablet 1 tablet (10 mg/tab.) once a day. And all received the adiaphorous drug with the dosage-form mimic to that used in the tested group. The therapeutic course was 4 weeks for both groups. RESULTS: The markedly effective rate and the total effective rate in reducing blood pressure was 58.65% and 79.81% respectively in the tested group, and 60.51% and 78.34% respectively in the control group; while the markedly effective rate and the total effective rate for alleviating TCM syndrome was 21.15% and 78.85% in the tested group, and 25.48% and 86.62% in the control group respectively. Comparisons between the two groups showed insignificant difference (P > 0.05). CONCLUSION: ZHC has good efficacy and is safety in treating hypertension.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Hipertensão/tratamento farmacológico , Fitoterapia , Deficiência da Energia Yin/tratamento farmacológico , Adulto , Idoso , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Benzazepinas/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Feminino , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Síndrome , Comprimidos , Deficiência da Energia Yin/patologia
8.
Cancer Epidemiol Biomarkers Prev ; 14(5): 1230-5, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15894677

RESUMO

I-compounds are bulky covalent DNA modifications that are derived from metabolic intermediates of nutrients. Some I-compounds may play protective roles against cancer, aging, and degenerative diseases. Many carcinogens and tumor promoters significantly reduce I-compound levels gradually during carcinogenesis. Colon cancer is the second leading cause of cancer death in the United States, whereas cancer of the small intestine is relatively rare. Here we have studied levels of I-compounds in DNA of colon and duodenum of male Sprague-Dawley rats treated with azoxymethane. The effects of dietary lipids (fish oil or corn oil) on colon and duodenal DNA I-compounds were also investigated. Rats fed a diet containing fish oil or corn oil were treated with 15 mg/kg azoxymethane. Animals were terminated 0, 6, 9, 12, or 24 hours after injection. I-compound levels were analyzed by the nuclease P1-enhanced (32)P-postlabeling assay. Rats treated with azoxymethane displayed lower levels of I-compounds in colon DNA compared with control groups (0 hour). However, I-compound levels in duodenal DNA were not diminished after azoxymethane treatment. Animals fed a fish oil diet showed higher levels of I-compounds in colonic DNA compared with corn oil groups (mean adduct levels for fish and corn oil groups were 13.35 and 10.69 in 10(9) nucleotides, respectively, P = 0.034). Taken together, these results support claims that fish oil, which contains a high level of omega-3 polyunsaturated fatty acids, may have potent chemopreventive effects on carcinogen-induced colon cancer. The fact that duodenal I-compounds were not diminished by azoxymethane treatment may have been due to the existence of tissue-specific factors protecting against carcinogenesis. In conclusion, our observations show that endogenous DNA adducts may serve not only as sensitive biomarkers in carcinogenesis and cancer prevention studies, but are also helpful to further our understanding of the chemopreventive properties of omega-3 fatty acids and mechanisms of carcinogenesis.


Assuntos
Azoximetano/metabolismo , Carcinógenos/metabolismo , Neoplasias do Colo/genética , Neoplasias do Colo/prevenção & controle , Óleo de Milho/farmacologia , Adutos de DNA/farmacologia , Dano ao DNA/efeitos dos fármacos , Neoplasias Duodenais/genética , Neoplasias Duodenais/prevenção & controle , Óleos de Peixe/farmacologia , Análise de Variância , Animais , Azoximetano/administração & dosagem , Biomarcadores , Carcinógenos/administração & dosagem , Neoplasias do Colo/metabolismo , Neoplasias Duodenais/metabolismo , Masculino , Modelos Animais , Nucleotídeos , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Endonucleases Específicas para DNA e RNA de Cadeia Simples
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