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1.
Molecules ; 26(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34443598

RESUMO

Apocynin (APO) is a known multi-enzymatic complexed compound, employed as a viable NADPH oxidase (NOX) inhibitor, extensively used in both traditional and modern-day therapeutic strategies to combat neuronal disorders. However, its therapeutic efficacy is limited by lower solubility and lesser bioavailability; thus, a suitable nanocarrier system to overcome such limitations is needed. The present study is designed to fabricate APO-loaded polymeric nanoparticles (APO-NPs) to enhance its therapeutic efficacy and sustainability in the biological system. The optimized APO NPs in the study exhibited 103.6 ± 6.8 nm and -13.7 ± 0.43 mV of particle size and zeta potential, respectively, along with further confirmation by TEM. In addition, the antioxidant (AO) abilities quantified by DPPH and nitric oxide scavenging assays exhibited comparatively higher AO potential of APO-NPs than APO alone. An in-vitro release profile displayed a linear diffusion pattern of zero order kinetics for APO from the NPs, followed by its cytotoxicity evaluation on the PC12 cell line, which revealed minimal toxicity with higher cell viability, even after treatment with a stress inducer (H2O2). The stability of APO-NPs after six months showed minimal AO decline in comparison to APO only, indicating that the designed nano-formulation enhanced therapeutic efficacy for modulating NOX-mediated ROS generation.


Assuntos
Acetofenonas/química , Acetofenonas/farmacologia , Peróxido de Hidrogênio/farmacologia , NADPH Oxidases/metabolismo , Nanopartículas/química , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Neurônios/citologia , Neurônios/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Células PC12 , Ratos
2.
Molecules ; 26(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34443563

RESUMO

Paeonol is a naturally existing bioactive compound found in the root bark of Paeonia suffruticosa and it is traditionally used in Chinese medicine for the prevention and management of cardiovascular diseases. To date, a great deal of studies has been reported on the pharmacological effects of paeonol and its mechanisms of action in various diseases and conditions. In this review, the underlying mechanism of action of paeonol in cardiovascular disease has been elucidated. Recent studies have revealed that paeonol treatment improved endothelium injury, demoted inflammation, ameliorated oxidative stress, suppressed vascular smooth muscle cell proliferation, and repressed platelet activation. Paeonol has been reported to effectively protect the cardiovascular system either employed alone or in combination with other traditional medicines, thus, signifying it could be a hypothetically alternative or complementary atherosclerosis treatment. This review summarizes the biological and pharmacological activities of paeonol in the treatment of cardiovascular diseases and its associated underlying mechanisms for a better insight for future clinical practices.


Assuntos
Acetofenonas/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Acetofenonas/uso terapêutico , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologia , Humanos
3.
Life Sci ; 284: 119911, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34450167

RESUMO

AIM: Male reproductive toxicity is becoming of growing significance due to clinical chemotherapy usage. Methotrexate (MTX) is an anti-folate used on a large scale for different tumors and autoimmune conditions. Despite its wide clinical use, MTX is associated with severe testicular intoxication. The exact underlying mechanism is unclear. METHODS: Our study was conducted to explore the pathogenesis mechanism of MTX-induced testicular damage and the potential testicular protective effects of apocynin (APO) on testicular injury induced by single i.p. MTX (20 mg/kg). APO was administered orally (100 mg/kg) for ten days. RESULTS: As compared to rats given MTX alone, co-administration of MTX with APO demonstrated multiple beneficial effects evidenced by a marked increase in testosterone, FSH, and LH and significantly restored testes histopathological alterations. Mechanistically, APO restored antioxidant status through up-regulation of Nrf2, cytoglobin, PPAR-γ, SIRT1, AKT, and p-AKT, while effectively lowering Keap-1. Moreover, APO significantly attenuated inflammation by down-regulating NF-κB-p65, iNOS, and TLR4 expressions confirmed by in-silico evidence. Additionally, network pharmacology analysis, a bioinformatics approach, was used to decipher various cellular processes' molecular mechanisms. SIGNIFICANCE: The current investigation proves the beneficial effects of APO in MTX-associated testicular damage through activation of cytoglobin, Keap-1/Nrf2/AKT, PPAR-γ, SIRT1, and suppressing of TLR4/NF-κB-p65 signal. Our data collectively encourage extending the investigation to the clinical setting to explore APO effects in MTX-treated patients.


Assuntos
Acetofenonas/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Metotrexato/efeitos adversos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Testículo/patologia , Receptor 4 Toll-Like/metabolismo , Acetofenonas/química , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Inflamação/patologia , Interleucina-6/metabolismo , Masculino , Simulação de Acoplamento Molecular , Óxido Nítrico/metabolismo , Oxidantes/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Peroxidase/metabolismo , Mapas de Interação de Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Testículo/efeitos dos fármacos , Testículo/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
4.
Molecules ; 26(12)2021 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-34205355

RESUMO

Rottlerin is a natural product consisting of chalcone and flavonoid scaffolds, both of which have previously shown quorum sensing (QS) inhibition in various bacteria. Therefore, the unique rottlerin scaffold highlights great potential in inhibiting the QS system of Pseudomonas aeruginosa. Rottlerin analogues were synthesised by modifications at its chalcone- and methylene-bridged acetophenone moieties. The synthesis of analogues was achieved using an established five-step synthetic strategy for chalcone derivatives and utilising the Mannich reaction at C6 of the chromene to construct morpholine analogues. Several pyranochromene chalcone derivatives were also generated using aldol conditions. All the synthetic rottlerin derivatives were screened for QS inhibition and growth inhibition against the related LasR QS system. The pyranochromene chalcone structures displayed high QS inhibitory activity with the most potent compounds, 8b and 8d, achieving QS inhibition of 49.4% and 40.6% and no effect on bacterial growth inhibition at 31 µM, respectively. Both compounds also displayed moderate biofilm inhibitory activity and reduced the production of pyocyanin.


Assuntos
Acetofenonas/farmacologia , Benzopiranos/farmacologia , Produtos Biológicos/farmacologia , Percepção de Quorum/efeitos dos fármacos , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Flavonoides/farmacologia , Testes de Sensibilidade Microbiana/métodos , Pseudomonas aeruginosa/efeitos dos fármacos , Piocianina/farmacologia
5.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281274

RESUMO

It has been recognized that serotonin 2A receptor (5-HT2A) agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI) impairs serotonergic homeostasis. However, the mechanism of DOI-induced serotonergic behaviors remains to be explored. Moreover, little is known about therapeutic interventions against serotonin syndrome, although evidence suggests that ginseng might possess modulating effects on the serotonin system. As ginsenoside Re (GRe) is well-known as a novel antioxidant in the nervous system, we investigated whether GRe modulates 5-HT2A receptor agonist DOI-induced serotonin impairments. We proposed that protein kinase Cδ (PKCδ) mediates serotonergic impairments. Treatment with GRe or 5-HT2A receptor antagonist MDL11939 significantly attenuated DOI-induced serotonergic behaviors (i.e., overall serotonergic syndrome behaviors, head twitch response, hyperthermia) by inhibiting mitochondrial translocation of PKCδ, reducing mitochondrial glutathione peroxidase activity, mitochondrial dysfunction, and mitochondrial oxidative stress in wild-type mice. These attenuations were in line with those observed upon PKCδ inhibition (i.e., pharmacologic inhibitor rottlerin or PKCδ knockout mice). Furthermore, GRe was not further implicated in attenuation mediated by PKCδ knockout in mice. Our results suggest that PKCδ is a therapeutic target for GRe against serotonergic behaviors induced by DOI.


Assuntos
Ginsenosídeos/farmacologia , Proteína Quinase C-delta/metabolismo , Antagonistas da Serotonina/farmacologia , Síndrome da Serotonina/prevenção & controle , Acetofenonas/farmacologia , Anfetaminas/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Benzopiranos/farmacologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/farmacologia , Proteína Quinase C-delta/deficiência , Proteína Quinase C-delta/genética , Inibidores de Proteínas Quinases/farmacologia , Serotonina/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , Síndrome da Serotonina/induzido quimicamente , Síndrome da Serotonina/fisiopatologia
6.
J Chem Ecol ; 47(8-9): 777-787, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34287796

RESUMO

The "River Disease" (RD), a disorder impacting honeybee colonies located close to waterways with abundant riparian vegetation (including Sebastiania schottiana, Euphorbiaceae), kills newly hatched larvae. Forager bees from RD-affected colonies collect honeydew excretions from Epormenis cestri (Hemiptera: Flatidae), a planthopper feeding on trees of S. schottiana. First-instar honeybee larvae fed with this honeydew died. Thus, we postulated that the nectars of RD-affected colonies had a natural toxin coming from either E. cestri or S. schottiana. An untargeted metabolomics characterization of fresh nectars extracts from colonies with and without RD allowed to pinpoint xanthoxylin as one of the chemicals present in higher amounts in nectar from RD-affected colonies than in nectars from healthy colonies. Besides, xanthoxylin was also found in the aerial parts of S. schottiana and the honeydew excreted by E. cestri feeding on this tree. A larva feeding assay where xanthoxylin-enriched diets were offered to 1st instar larvae showed that larvae died in the same proportion as larvae did when offered enriched diets with nectars from RD-colonies. These findings demonstrate that a xenobiotic can mimic the RD syndrome in honeybee larvae and provide evidence of an interspecific flow of xanthoxylin among three trophic levels. Further, our results give information that can be considered when implementing measures to control this honeybee disease.


Assuntos
Acetofenonas/análise , Abelhas/fisiologia , Euphorbiaceae/química , Acetofenonas/farmacologia , Animais , Abelhas/crescimento & desenvolvimento , Dieta/veterinária , Análise Discriminante , Euphorbiaceae/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Larva/efeitos dos fármacos , Larva/fisiologia , Análise dos Mínimos Quadrados , Espectroscopia de Ressonância Magnética , Metabolômica/métodos , Componentes Aéreos da Planta/química , Componentes Aéreos da Planta/metabolismo , Néctar de Plantas/química
7.
Biomolecules ; 11(6)2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203655

RESUMO

Anxiety disorders are common mental health diseases affecting up to 7% of people around the world. Stress is considered one of the major environmental risk factors to promote anxiety disorders through mechanisms involving epigenetic changes. Moreover, alteration in redox balance and increased reactive oxygen species (ROS) production have been detected in anxiety patients and in stressed-animal models of anxiety. Here we tested if the administration of apocynin, a natural origin antioxidant, may prevent the anxiety-like phenotype and reduction of histone acetylation induced by a subchronic forced swimming stress (FSS) paradigm. We found that apocynin prevented the enhanced latency time in the novelty-suppressed feeding test, and the production of malondialdehyde induced by FSS. Moreover, apocynin was able to block the upregulation of p47phox, a key subunit of the NADPH oxidase complex. Finally, apocynin prevented the rise of hippocampal Hdac1, Hdac4 and Hdac5, and the reduction of histone-3 acetylation levels promoted by FSS exposure. In conclusion, our results provide evidence that apocynin reduces the deleterious effect of stress and suggests that oxidative stress may regulate epigenetic mechanisms.


Assuntos
Acetofenonas/farmacologia , Transtornos de Ansiedade/enzimologia , Comportamento Animal/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hipocampo/enzimologia , Histona Desacetilases/biossíntese , Estresse Psicológico/enzimologia , Animais , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/fisiopatologia , Hipocampo/fisiopatologia , Masculino , Camundongos , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/fisiopatologia
8.
Chem Biol Interact ; 345: 109558, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34147486

RESUMO

m-(Tert-butyl) trifluoroacetophenone (TFK), a slow-binding inhibitor of acetylcholinesterase (AChE), a transition state analog of acetylcholine, was investigated as a potential neuroprotectant of central and peripheral AChE against organophosphate paraoxon (POX) toxicity. Acute toxicity and pharmacological effects of TFK were investigated on mice and rats. Intraperitoneal administered TFK has low acute toxicity in mice (LD50 ≈ 19 mg/kg). Effects on motor function as investigated by rotarod and open field tests showed that TFK up to 5 mg/kg did not alter motor coordination and stereotypical exploration behavior of mice. Passive avoidance test showed that 1 or 5 mg/kg TFK restored memory impairment in scopolamine-induced Alzheimer's disease-like dementia in rats. Pretreatment of mice with 5 mg/kg TFK, 2-3 h before challenge by 2xLD50 POX provided a modest and short protection against POX toxicity. Futhermore, analysis of POX-induced neuronal degeneration by using fluoro-jade B staining showed that TFK pretreatment, at the dose 5 mg/kg before POX challenge, significantly reduced the density of apoptotic cells in hippocampus and entorhinal cortex of mice. Thus, TFK is capable of reducing POX-induced neurotoxicity.


Assuntos
Acetofenonas/química , Acetofenonas/farmacologia , Acetilcolina/análogos & derivados , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Transtornos da Memória/tratamento farmacológico , Paraoxon/toxicidade , Acetofenonas/uso terapêutico , Animais , Inibidores da Colinesterase/uso terapêutico , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/fisiopatologia , Camundongos
9.
Int J Mol Sci ; 22(9)2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066458

RESUMO

Paeonia suffruticosa has been extensively used as a traditional medicine with various beneficial effects; paeonolide (PALI) was isolated from its dried roots. This study aimed to investigate the novel effects and mechanisms of PALI in pre-osteoblasts. Here, cell viability was evaluated using an MTT assay. Early and late osteoblast differentiation was examined by analyzing the activity of alkaline phosphatase (ALP) and by staining it with Alizarin red S (ARS). Cell migration was assessed using wound healing and Boyden chamber assays. Western blot and immunofluorescence analyses were used to examine the intracellular signaling pathways and differentiation proteins. PALI (0.1, 1, 10, 30, and 100 µM) showed no cytotoxic or proliferative effects in pre-osteoblasts. In the absence of cytotoxicity, PALI (1, 10, and 30 µM) promoted wound healing and transmigration during osteoblast differentiation. ALP staining demonstrated that PALI (1, 10, and 30 µM) promoted early osteoblast differentiation in a dose-dependent manner, and ARS staining showed an enhanced mineralized nodule formation, a key indicator of late osteoblast differentiation. Additionally, low concentrations of PALI (1 and 10 µM) increased the bone morphogenetic protein (BMP)-Smad1/5/8 and Wnt-ß-catenin pathways in osteoblast differentiation. Particularly, PALI (1 and 10 µM) increased the phosphorylation of ERK1/2 compared with BMP2 treatment, an FDA-approved drug for bone diseases. Furthermore, PALI-mediated early and late osteoblast differentiation was abolished in the presence of the ERK1/2 inhibitor U0126. PALI-induced RUNX2 (Cbfa1) expression and nuclear localization were also attenuated by blocking the ERK1/2 pathway during osteoblast differentiation. We suggest that PALI has biologically novel activities, such as enhanced osteoblast differentiation and bone mineralization mainly through the intracellular ERK1/2-RUNX2 signaling pathway, suggesting that PALI might have therapeutic action and aid the treatment and prevention of bone diseases, such as osteoporosis and periodontitis.


Assuntos
Acetofenonas/farmacologia , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Osteoblastos/metabolismo , Osteogênese , Animais , Proteína Morfogenética Óssea 2/metabolismo , Calcificação Fisiológica/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Proteína Wnt3/metabolismo
10.
Phytother Res ; 35(8): 4499-4510, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33969557

RESUMO

Cyclophosphamide (CP) is a medication used as an anticancer drug and to suppress the immune system. However, its clinical applications are restricted because of the toxic and adverse side effects. The present study investigated the protective effect of acetovanillone (AV), a natural NADPH oxidase inhibitor, against acute lung injury (ALI) induced by CP. Rats were administered AV (100 mg/kg) for 10 days and a single injection of CP (200 mg/kg) at day 7. At the end of the experiment, the animals were sacrificed, and lung samples were collected for analyses. CP caused ALI manifested by the histopathological alterations. Lipid peroxidation and NADPH oxidase activity were increased, whereas GSH and antioxidant enzymes were decreased in the lung of CP-intoxicated rats. Oral administration of AV prevented CP-induced lung injury and oxidative stress and enhanced antioxidant defenses. AV downregulated Keap1 and upregulated Nrf2, GCLC, HO-1, and SOD3 mRNA. In addition, AV boosted the expression of PI3K, Akt, mTOR, and cytoglobin. In vitro, AV showed a synergistic anticancer effect when combined with CP. In conclusion, AV protected against CP-induced ALI by attenuating oxidative stress and boosting Nrf2/HO-1 and PI3K/Akt/mTOR signaling. Therefore, AV might represent a promising adjuvant to prevent lung injury in patients receiving CP.


Assuntos
Acetofenonas/farmacologia , Lesão Pulmonar Aguda , Transdução de Sinais/efeitos dos fármacos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/prevenção & controle , Animais , Ciclofosfamida/toxicidade , Proteína 1 Associada a ECH Semelhante a Kelch , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Ratos , Ratos Wistar , Serina-Treonina Quinases TOR
11.
Nat Commun ; 12(1): 2507, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947863

RESUMO

Notch1 is a crucial oncogenic driver in T-cell acute lymphoblastic leukemia (T-ALL), making it an attractive therapeutic target. However, the success of targeted therapy using γ-secretase inhibitors (GSIs), small molecules blocking Notch cleavage and subsequent activation, has been limited due to development of resistance, thus restricting its clinical efficacy. Here, we systematically compare GSI resistant and sensitive cell states by quantitative mass spectrometry-based phosphoproteomics, using complementary models of resistance, including T-ALL patient-derived xenografts (PDX) models. Our datasets reveal common mechanisms of GSI resistance, including a distinct kinase signature that involves protein kinase C delta. We demonstrate that the PKC inhibitor sotrastaurin enhances the anti-leukemic activity of GSI in PDX models and completely abrogates the development of acquired GSI resistance in vitro. Overall, we highlight the potential of proteomics to dissect alterations in cellular signaling and identify druggable pathways in cancer.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Oligopeptídeos/farmacologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Proteína Quinase C/metabolismo , Receptor Notch1/antagonistas & inibidores , Acetofenonas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Antineoplásicos/uso terapêutico , Benzopiranos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Imunoprecipitação da Cromatina , Cromatografia Líquida de Alta Pressão , Resistencia a Medicamentos Antineoplásicos/genética , Ontologia Genética , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos NOD , Fosforilação , Análise Serial de Proteínas , Biossíntese de Proteínas/efeitos dos fármacos , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/genética , Proteínas Quinases/metabolismo , Proteômica , Receptor Notch1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Espectrometria de Massas em Tandem , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Int J Mol Sci ; 22(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805516

RESUMO

Reactive oxygen species (ROS) metabolism is regulated by the oxygen-mediated enzyme reaction and antioxidant mechanism within cells under physiological conditions. Xanthine oxidoreductase (XOR) exhibits two inter-convertible forms (xanthine oxidase (XO) and xanthine dehydrogenase (XDH)), depending on the substrates. XO uses oxygen as a substrate and generates superoxide (O2•-) in the catalytic pathway of hypoxanthine. We previously showed that superoxide dismutase 1 (SOD1) loss induced various aging-like pathologies via oxidative damage due to the accumulation of O2•- in mice. However, the pathological contribution of XO-derived O2•- production to aging-like tissue damage induced by SOD1 loss remains unclear. To investigate the pathological significance of O2•- derived from XOR in Sod1-/- mice, we generated Sod1-null and XO-type- or XDH-type-knock-in (KI) double-mutant mice. Neither XO-type- nor XDH-type KI mutants altered aging-like phenotypes, such as anemia, fatty liver, muscle atrophy, and bone loss, in Sod1-/- mice. Furthermore, allopurinol, an XO inhibitor, or apocynin, a nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitor, failed to improve aging-like tissue degeneration and ROS accumulation in Sod1-/- mice. These results showed that XOR-mediated O2•- production is relatively uninvolved in the age-related pathologies in Sod1-/- mice.


Assuntos
Envelhecimento/fisiologia , Superóxido Dismutase-1/genética , Superóxidos/metabolismo , Xantina Desidrogenase/metabolismo , Acetofenonas/farmacologia , Envelhecimento/efeitos dos fármacos , Alopurinol/farmacologia , Anemia/genética , Animais , Fígado Gorduroso/genética , Camundongos Mutantes , Atrofia Muscular/genética , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/metabolismo , Superóxido Dismutase-1/metabolismo , Xantina Desidrogenase/antagonistas & inibidores , Xantina Desidrogenase/genética
13.
Clin Exp Hypertens ; 43(5): 462-473, 2021 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-33775188

RESUMO

BACKGROUND: Signal transduction of Angiotensin II (Ang II) induced autophagy and its role in Ang II-induced dysfunction of HUVECs are still unclear. METHODS: HUVECs are stimulated with different doses of Ang II (10-9-10-5 mol/L) for different time (6-48 hours). Autophagy-related protein markers: LC3, Beclin-1 and SQSTM1/p62 are measured by western blot. RESULTS: Incubation with Ang II increases autophagic flux (Beclin-1, autophagosomes formation, and degradation of SQSTM1/p62, LC3-I). Increased autophagic levels are inhibited by pretreatment with Ang II type 1 receptor (AT1) blocker (Candesartan), NADPH Oxidase inhibitor (apocycin), mitochondrial KATP channels inhibitor (5-hydroxydecanoate, 5HD). 3-Methyladenine (inhibitors of autophagy) and rapamycin (activator of autophagy) respectively inhibits or activates Ang II-induced autophagy levels. Ang II decreases phosphorylation of endothelial nitric oxide synthase (eNOS) and NO production in HUVECs. L-NAME (NOS inhibitor) totally mimics the actions of Ang II on eNOS, NO production and autophagy levels. Rapamycin further decreases NO production combined with Ang II. Silence Atg5 completely reverses Ang II-activated autophagy levels. CONCLUSIONS: Our results demonstrate that Ang II stimulation increases autophagy levels via AT1 receptor, NADPH oxidase, mitochondrial KATP channel, eNOS, Atg5 signal pathway in HUVECs, and activation of autophagy contributes to Ang II induced dysfunction of HUVECs.


Assuntos
Angiotensina II/toxicidade , Autofagia , Células Endoteliais da Veia Umbilical Humana/patologia , Acetofenonas/farmacologia , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Autofagia/efeitos dos fármacos , Proteínas Relacionadas à Autofagia/metabolismo , Benzimidazóis/farmacologia , Compostos de Bifenilo/farmacologia , Ácidos Decanoicos/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Hidroxiácidos/farmacologia , Modelos Biológicos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Tetrazóis/farmacologia , Fatores de Tempo
14.
Mol Med Rep ; 23(6)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33786614

RESUMO

Cervical cancer is a common public health issue with high morbidity worldwide. Paeonol (Pae) has been recognized as a traditional Chinese medicine used for the treatment of various cancer types. However, whether Pae could exert a protective effect on cervical cancer remains to be investigated. The aim of the present study was to explore the role of Pae in cervical cancer cells and identify the potential mechanism. Cell Counting Kit­8 and colony­formation assays were conducted to test the proliferation of HeLa cells. Additionally, wound healing and transwell assays were used to detect the migratory and invasive abilities of cells. The plasmid that overexpressed 5­lipoxygenase (5­LO) or control vector was constructed and transfected into the cells. Subsequently, flow cytometry was used to monitor the apoptotic rate of cells. The expression levels of apoptosis­associated proteins and 5­LO were detected using western blot analysis. Reverse transcription­quantitative PCR analysis detected the expression of 5­LO. Pae inhibited the proliferation, invasion and migration of HeLa cells, promoted cell apoptosis and downregulated the expression of 5­LO. Overexpression of 5­LO, however, attenuated these effects. Thus, Pae could inhibit the proliferation, migration and invasion, as well as promote apoptosis of HeLa cells by regulating the expression of 5­LO.


Assuntos
Acetofenonas/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Araquidonato 5-Lipoxigenase/metabolismo , Movimento Celular/efeitos dos fármacos , Araquidonato 5-Lipoxigenase/genética , Proliferação de Células/efeitos dos fármacos , Células HeLa , Humanos
15.
Histochem Cell Biol ; 155(6): 699-718, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33755775

RESUMO

Exposure to airborne organic dust (OD), rich in microbial pathogen-associated molecular patterns (PAMPs), is shown to induce lung inflammation. A common manifestation in lung inflammation is altered mitochondrial structure and bioenergetics that regulate mitochondrial ROS (mROS) and feed a vicious cycle of mitochondrial dysfunction. The role of mitochondrial dysfunction in other airway diseases is well known. However, whether OD exposure induces mitochondrial dysfunction remains elusive. Therefore, we tested a hypothesis that organic dust extract (ODE) exposure induces mitochondrial stress using a human monocytic cell line (THP1). We examined whether co-exposure to ethyl pyruvate (EP) or mitoapocynin (MA) could rescue ODE exposure induced mitochondrial changes. Transmission electron micrographs showed significant differences in cellular and organelle morphology upon ODE exposure. ODE exposure with and without EP co-treatment increased the mtDNA leakage into the cytosol. Next, ODE exposure increased PINK1, Parkin, cytoplasmic cytochrome c levels, and reduced mitochondrial mass and cell viability, indicating mitophagy. MA treatment was partially protective by decreasing Parkin expression, mtDNA and cytochrome c release and increasing cell viability.


Assuntos
Poeira/análise , Exposição Ambiental/análise , Mitocôndrias/metabolismo , Monócitos/metabolismo , Acetofenonas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Monitoramento Ambiental , Humanos , Estresse Oxidativo/efeitos dos fármacos , Piruvatos/farmacologia
16.
Oxid Med Cell Longev ; 2021: 6643171, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33628369

RESUMO

Background: Perinatal hypoxia is a universal cause of death and neurological deficits in neonates worldwide. Activation of microglial NADPH oxidase 2 (NOX2) leads to oxidative stress and neuroinflammation, which may contribute to hypoxic damage in the developing brain. Dexmedetomidine has been reported to exert potent neuroprotection in several neurological diseases, but the mechanism remains unclear. We investigated whether dexmedetomidine acts through microglial NOX2 to reduce neonatal hypoxic brain damage. Methods: The potential role of microglial NOX2 in dexmedetomidine-mediated alleviation of hypoxic damage was evaluated in cultured BV2 microglia and neonatal rats subjected to hypoxia. In vivo, neonatal rats received dexmedetomidine (25 µg/kg, i.p.) 30 min before or immediately after hypoxia (5% O2, 2 h). Apocynin-mediated NOX inhibition and lentivirus-mediated NOX2 overexpression were applied to further assess the involvement of microglial NOX2 activation. Results: Pre- or posttreatment with dexmedetomidine alleviated hypoxia-induced cognitive impairment, restored damaged synapses, and increased postsynaptic density-95 and synaptophysin protein expression following neonatal hypoxia. Importantly, dexmedetomidine treatment suppressed hypoxia-induced microglial NOX2 activation and subsequent oxidative stress and the neuroinflammatory response, as reflected by reduced 4-hydroxynonenal and ROS accumulation, and decreased nuclear NF-κB p65 and proinflammatory cytokine levels in cultured BV2 microglia and the developing hippocampus. In addition, treating primary hippocampal neurons with conditioned medium (CM) from hypoxia-activated BV2 microglia resulted in neuronal damage, which was alleviated by CM from dexmedetomidine-treated microglia. Moreover, the neuroprotective effect of dexmedetomidine was reversed in NOX2-overexpressing BV2 microglia and diminished in apocynin-pretreated neonatal rats. Conclusion: Dexmedetomidine targets microglial NOX2 to reduce oxidative stress and neuroinflammation and subsequently protects against hippocampal synaptic loss following neonatal hypoxia.


Assuntos
Disfunção Cognitiva/enzimologia , Disfunção Cognitiva/etiologia , Dexmedetomidina/farmacologia , Hipocampo/patologia , Hipóxia/complicações , Microglia/enzimologia , NADPH Oxidase 2/metabolismo , Sinapses/patologia , Acetofenonas/farmacologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Disfunção Cognitiva/patologia , Citocinas/metabolismo , Ativação Enzimática/efeitos dos fármacos , Hipocampo/ultraestrutura , Mediadores da Inflamação/metabolismo , Microglia/efeitos dos fármacos , Microglia/patologia , Microglia/ultraestrutura , Modelos Biológicos , NADPH Oxidase 2/antagonistas & inibidores , NF-kappa B/metabolismo , Neuroproteção/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/ultraestrutura
17.
J Cell Mol Med ; 25(6): 2885-2899, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33534963

RESUMO

Inflammation is a biological process that exists in a large number of diseases. If the magnitude or duration of inflammation becomes uncontrolled, inflammation may cause pathological damage to the host. HMGB1 and NF-κB have been shown to play pivotal roles in inflammation-related diseases. New drugs aimed at inhibiting HMGB1 expression have become a key research focus. In the present study, we showed that paeonol (Pae), the main active component of Paeonia suffruticosa, decreases the expression of inflammatory cytokines and inhibits the translocation of HMGB1 induced by lipopolysaccharide (LPS). By constructing HMGB1-overexpressing (HMGB1+ ) and HMGB1-mutant (HMGB1m ) RAW264.7 cells, we found that the nuclear HMGB1 could induce an LPS-tolerant state in RAW264.7 cells and that paeonol had no influence on the expression of inflammatory cytokines in HMGB1m RAW264.7 cells. In addition, the anti-inflammatory property of paeonol was lost in HMGB1 conditional knockout mice, indicating that HMGB1 is a target of paeonol and a mediator through which paeonol exerts its anti-inflammatory function. Additionally, we also found that HMGB1 and P50 competitively bound with P65, thus inactivating the NF-κB pathway. Our research confirmed the anti-inflammation property of paeonol and suggests that inhibiting the translocation of HMGB1 could be a new strategy for treating inflammation.


Assuntos
Acetofenonas/farmacologia , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Proteína HMGB1/metabolismo , Acetofenonas/química , Animais , Anti-Inflamatórios/química , Núcleo Celular/metabolismo , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Proteína HMGB1/química , Proteína HMGB1/genética , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Knockout , Modelos Moleculares , NF-kappa B/metabolismo , Transporte Proteico , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
18.
Molecules ; 26(3)2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525713

RESUMO

The dichloromethane extract from leaves of Melicope barbigera (Rutaceae), endemic to the Hawaiian island of Kaua'i, yielded four new and three previously known acetophenones and 2H-chromenes, all found for the first time in M. barbigera. The structures of the new compounds obtained from the dichloromethane extract after purification by chromatographic methods were unambiguously elucidated by spectroscopic analyses including 1D/2D NMR spectroscopy and HRESIMS. The absolute configuration was determined by modified Mosher's method. Compounds 2, 4 and the mixture of 6 and 7 exhibited moderate cytotoxic activities against the human ovarian cancer cell line A2780 with IC50 values of 30.0 and 75.7 µM for 2 and 4, respectively, in a nuclear shrinkage cytotoxicity assay.


Assuntos
Acetofenonas/química , Benzopiranos/química , Folhas de Planta/química , Rutaceae/química , Acetofenonas/farmacologia , Benzopiranos/farmacologia , Linhagem Celular Tumoral , Feminino , Hawaii , Humanos , Espectroscopia de Ressonância Magnética/métodos , Cloreto de Metileno/química , Neoplasias Ovarianas/tratamento farmacológico
19.
Life Sci ; 271: 119202, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33577853

RESUMO

BACKGROUND: Diabetic neuropathy is one of the most common microvascular complication of diabetes. It is associated with neuronal dysfunction and pain. Paeonol is an important natural product reported for its antioxidant, anti-inflammatory and antidiabetic activities. AIM: The present research was planned to study effect of paeonol in diabetic peripheral neuropathy in rats. METHODS: Diabetes was induced in Sprague Dawley rats by using Streptozotocin (55 mg/kg, i.p.). After six weeks, diabetic animals were treated daily with paeonol at a dose of 50, 100 and 200 mg/kg for four weeks. At the end of the treatment, plasma glucose, mechanical allodynia, mechanical hyperalgesia, thermal hyperalgesia and nerve conduction velocities were recorded. Oxidative stress parameters were studied in sciatic nerve. Histopathology study of sciatic nerve, NF-κB and MCP-1 expression were also studied at the end of study. KEY FINDINGS: Paeonol treatment significantly lowered the plasma glucose levels, mechanical allodynia, mechanical hyperalgesia and thermal hyperalgesia as compared to diabetic control group. Paeonol treatment also enhanced the motor and sensory nerve conduction velocity. Paeonol treated diabetic animals showed significant changes in oxidative stress parameters. Histopathology study indicated that paeonol treatment prevented the neuronal damage, lowered demyelination and leukocyte infiltration. NF-κB and MCP-1 expression was significantly decreased in sciatic nerve of diabetic animals treated with paeonol. SIGNIFICANCE: Results of the present study indicate that paeonol may be considered as effective option for management of diabetic neuropathy.


Assuntos
Acetofenonas/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Condução Nervosa/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Acetofenonas/farmacologia , Animais , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Masculino , Condução Nervosa/fisiologia , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
20.
Mol Cell Biochem ; 476(5): 2047-2059, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33515200

RESUMO

Mitoapocynin is a triphenylphosphonium conjugated derivative of apocynin that specifically locates to the mitochondria. It has been developed as a mitochondrially targeted therapeutic antioxidant. We attempted to attenuate the mitochondrial ROS induced in H9c2 cardiac myoblast cells treated with norepinephrine. Mitoapocynin was a poor quencher of total ROS as detected by the fluoroprobe DCFH-DA. Using mitochondrial superoxide specific probe MitoSoxRed, we found that 5-10 µM mitoapocynin itself induces superoxide over and above that is generated by the norepinephrine treatment. A supposedly control molecule to mitoapocynin, the synthetic compound PhC11TPP, having the triphenylphosphonium group and a benzene moiety with C11 aliphatic chain spacer was also found to be a robust inducer of mitochondrial ROS. Subsequent assays with several cell lines viz., NIH3T3, HEK293, Neuro2A, MCF-7 and H9c2, showed that prolonged exposure to mitoapocynin induces cell death by apoptosis that can be partially prevented by the general antioxidant N-acetyl cysteine. Analyses of mitochondrial electron transport complexes by Blue Native Polyacrylamide gel electrophoresis showed that both mitoapocynin and PhC11TPP disrupt the mitochondrial Complex I and V, and in addition, PhC11TPP also damages the Complex IV. Our data thus highlights the limitations of the therapeutic use of mitoapocynin as an antioxidant.


Assuntos
Acetofenonas/farmacologia , Apoptose/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mioblastos Cardíacos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Células HEK293 , Humanos , Células MCF-7 , Camundongos , Células NIH 3T3
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