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1.
Eur J Pharmacol ; 967: 176370, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38320719

RESUMO

At least seven dominantly inherited spinocerebellar ataxias (SCA) are caused by expansions of polyglutamine (polyQ)-encoding CAG repeat. The misfolded and aggregated polyQ-expanded proteins increase reactive oxygen species (ROS), cellular toxicity, and neuroinflammation in the disease pathogenesis. In this study, we evaluated the anti-inflammatory potentials of coumarin derivatives LM-021, LMDS-1, LMDS-2, and pharmacological chaperone tafamidis using mouse BV-2 microglia and SCA3 ataxin-3 (ATXN3)/Q75-GFP SH-SY5Y cells. The four tested compounds displayed anti-inflammatory activity by suppressing nitric oxide (NO), interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α production, and CD68 antigen (CD68) and histocompatibility-2 (MHCII) expression in lipopolysaccharides (LPS)/interferon (IFN)-γ-stimulated BV-2 microglia. In retinoic acid-differentiated ATXN3/Q75-GFP-expressing SH-SY5Y cells inflamed with LPS/IFN-γ-primed BV-2 conditioned medium, treatment with test compounds mitigated the increased caspase 1 activity and lactate dehydrogenase release, reduced ROS and ATXN3/Q75 aggregation, and promoted neurite outgrowth. Examination of IL-1ß and IL-6-mediated signaling pathways revealed that LM-021, LMDS-1, LMDS-2, and tafamidis decreased NLR family pyrin domain containing 1 (NLRP1), c-Jun N-terminal kinase/c-Jun proto-oncogene (JNK/JUN), inhibitor of kappa B (IκBα)/P65, mitogen-activated protein kinase 14/signal transducer and activator of transcription 1 (P38/STAT1), and/or Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling. The study results suggest the potential of LM-021, LMDS-1, LMDS-2, and tafamidis in treating SCA3 and probable other polyQ diseases.


Assuntos
Doença de Machado-Joseph , Neuroblastoma , Animais , Humanos , Camundongos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Interleucina-1beta/antagonistas & inibidores , Interleucina-6 , Lipopolissacarídeos/farmacologia , Doença de Machado-Joseph/tratamento farmacológico , Doença de Machado-Joseph/genética , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
2.
Aging (Albany NY) ; 15(16): 8061-8089, 2023 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-37578928

RESUMO

Parkinson's disease (PD) is featured mainly by the loss of dopaminergic neurons and the presence of α-synuclein-containing aggregates in the substantia nigra of brain. The α-synuclein fibrils and aggregates lead to increased oxidative stress and neural toxicity in PD. Chronic inflammation mediated by microglia is one of the hallmarks of PD pathophysiology. In this report, we showed that coumarin-chalcone hybrid LM-021 and indole derivative NC009-1 reduced the expression of major histocompatibility complex-II, NLR family pyrin domain containing (NLRP) 3, caspase-1, inducible nitric oxide synthase, interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α in α-synuclein-activated mouse BV-2 microglia. Release of pro-inflammatory mediators including nitric oxide, IL-1ß, IL-6 and TNF-α was also mitigated. In BE(2)-M17 cells expressing A53T α-synuclein aggregates, LM-021 and NC009-1 reduced α-synuclein aggregation, neuroinflammation, oxidative stress and apoptosis, and promoted neurite outgrowth. These protective effects were mediated by downregulating NLRP1, IL-1ß and IL-6, and their downstream pathways including nuclear factor (NF)-κB inhibitor alpha (IκBα)/NF-κB P65 subunit (P65), c-Jun N-terminal kinase (JNK)/proto-oncogene c-Jun (JUN), mitogen-activated protein kinase 14 (P38)/signal transducer and activator of transcription (STAT) 1, and Janus kinase 2 (JAK2)/STAT3. The study results indicate LM-021 and NC009-1 as potential new drug candidates for PD.


Assuntos
Chalconas , Doença de Parkinson , Camundongos , Animais , alfa-Sinucleína/metabolismo , Chalconas/farmacologia , Interleucina-6/metabolismo , Inflamação/metabolismo , Estresse Oxidativo , Indóis/farmacologia , NF-kappa B/metabolismo , Doença de Parkinson/metabolismo , Microglia/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Cumarínicos/farmacologia , Lipopolissacarídeos/farmacologia
3.
Med Biol Eng Comput ; 58(5): 921-931, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32077012

RESUMO

3D printing allows product customisation to be cost efficient. This presents opportunity for innovation. This study investigated the effects of two modifications to the locking compression plate (LCP), an established orthopaedic implant used for fracture fixation. The first was to fill unused screw holes over the fracture site. The second was to reduce the Young's modulus by changing the microarchitecture of the LCP. Both are easily customisable with 3D printing. Finite element (FE) models of a fractured human tibia fixed with 4.5/5.0 mm LCPs were created. FE simulations were conducted to examine stress distribution within the LCPs. Next, a material sweep was performed to examine the effects of lowering the Young's modulus of the LCPs. Results showed at a knee joint loading of 3× body weight, peak stress was lowered in the modified broad LCP at 390.0 MPa compared to 565.1 MPa in the original LCP. It also showed that the Young's modulus of material could be lowered to 50 GPa before the minimum principal stresses increased exponentially. These findings suggested the modifications could lead to improved performances of fracture fixation, and therefore likely that other orthopaedic implants survivorship could also be enhanced by customisation via 3D printing. Graphical abstract.


Assuntos
Placas Ósseas , Fixação Interna de Fraturas/instrumentação , Impressão Tridimensional , Feminino , Análise de Elementos Finitos , Fixação Interna de Fraturas/métodos , Humanos , Pessoa de Meia-Idade , Tíbia/fisiologia , Tíbia/cirurgia , Fraturas da Tíbia/fisiopatologia , Fraturas da Tíbia/cirurgia
4.
Data Brief ; 4: 235-8, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26217796

RESUMO

The data in this article is related to the research article entitled, "Targeting of Multiple Oncogenic Signaling Pathways by Hsp90 Inhibitor Alone or in Combination with Berberine for Treatment of Colorectal Cancer" [1]. Overexpression of survivin induces resistance to various anticancer therapies such as chemotherapy and radiation therapy in colorectal cancer (CRC) cells. To determine significant correlations of biological functions/pathways with survivin, 4567 significant genes were analyzed from the GEO DataSet (GSE21815) of CRC and these were overlaid onto a global molecular network developed from information contained in the Ingenuity Pathway Analysis (IPA) database. The data here present the most significant disease and disordered biological functions, significant molecular/cellular functions and significant categories in physiological development/system functions which were associated with CRC. The top 10 canonical signaling pathways associated with CRC were categorize in order based on the level of statistical significance.

5.
Biochim Biophys Acta ; 1853(10 Pt A): 2261-72, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25982393

RESUMO

There is a wide range of drugs and combinations under investigation and/or approved over the last decade to treat colorectal cancer (CRC), but the 5-year survival rate remains poor at stages II-IV. Therefore, new, more-efficient drugs still need to be developed that will hopefully be included in first-line therapy or overcome resistance when it appears, as part of second- or third-line treatments in the near future. In this study, we revealed that heat shock protein 90 (Hsp90) inhibitors have high therapeutic potential in CRC according to combinative analysis of NCBI's Gene Expression Omnibus (GEO) repository and chemical genomic database of Connectivity Map (CMap). We found that second generation Hsp90 inhibitor, NVP-AUY922, significantly downregulated the activities of a broad spectrum of kinases involved in regulating cell growth arrest and death of NVP-AUY922-sensitive CRC cells. To overcome NVP-AUY922-induced upregulation of survivin expression which causes drug insensitivity, we found that combining berberine (BBR), a herbal medicine with potency in inhibiting survivin expression, with NVP-AUY922 resulted in synergistic antiproliferative effects for NVP-AUY922-sensitive and -insensitive CRC cells. Furthermore, we demonstrated that treatment of NVP-AUY922-insensitive CRC cells with the combination of NVP-AUY922 and BBR caused cell growth arrest through inhibiting CDK4 expression and induction of microRNA-296-5p (miR-296-5p)-mediated suppression of Pin1-ß-catenin-cyclin D1 signaling pathway. Finally, we found that the expression level of Hsp90 in tumor tissues of CRC was positively correlated with CDK4 and Pin1 expression levels. Taken together, these results indicate that combination of NVP-AUY922 and BBR therapy can inhibit multiple oncogenic signaling pathways of CRC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Berberina/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Isoxazóis/farmacologia , MicroRNAs/biossíntese , MicroRNAs/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Resorcinóis/farmacologia , Transdução de Sinais/genética
6.
RNA ; 21(3): 385-400, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25595716

RESUMO

In hepatitis B virus (HBV)-replicating hepatocytes, miR-130a expression was significantly reduced. In a reciprocal manner, miR-130a reduced HBV replication by targeting at two major metabolic regulators PGC1α and PPARγ, both of which can potently stimulate HBV replication. We proposed a positive feed-forward loop between HBV, miR-130a, PPARγ, and PGC1α. Accordingly, HBV can significantly enhance viral replication by reducing miR-130a and increasing PGC1α and PPARγ. NF-κB/p65 can strongly stimulate miR-130a promoter, while miR-130a can promote NF-κB/p65 protein level by reducing PPARγ and thus NF-κB/p65 protein degradation. We postulated another positive feed-forward loop between miR-130a and NF-κB/p65 via PPARγ. During liver inflammation, NF-κB signaling could contribute to viral clearance via its positive effect on miR-130a transcription. Conversely, in asymptomatic HBV carriers, persistent viral infection could reduce miR-130a and NF-κB expression, leading to dampened inflammation and immune tolerance. Finally, miR-130a could contribute to metabolic homeostasis by dual targeting PGC1α and PPARγ simultaneously.


Assuntos
Vírus da Hepatite B/genética , Hepatite B/genética , MicroRNAs/genética , PPAR gama/genética , Fatores de Transcrição/genética , Replicação do DNA/genética , Regulação da Expressão Gênica , Hepatite B/patologia , Hepatite B/virologia , Vírus da Hepatite B/patogenicidade , Hepatócitos/metabolismo , Hepatócitos/virologia , Humanos , MicroRNAs/metabolismo , PPAR gama/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Replicação Viral/genética
7.
J Proteome Res ; 10(10): 4522-34, 2011 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-21823664

RESUMO

The hepatitis C virus core protein (HCVc) forms the viral nucleocapsid and is involved in viral persistence and pathogenesis, possibly by interacting with host factors to modulate viral replication and cellular functions. Here, we identified 36 cellular protein candidates by one-dimensional SDS-PAGE and LC-MS/MS-based proteomics after affinity purification with HCVc174, a matured form of HCVc from HCV-1b genotype, tagged with biotin and calmodulin-binding peptide/protein A at N- and C-termini, respectively. By pull-down and confocal imaging techniques, we confirmed that heterogeneous nuclear ribonucleoprotein H1 (hnRNPH1), nuclear factor 45 (NF45), and C14orf166 are novel HCVc174-interacting host proteins, known to participate in mRNA metabolism, gene regulation, and microtubule organization, respectively. Unlike the other 2 proteins, NF45 interacted with HCVc174 in an RNA-dependent manner. These 3 proteins colocalized with ectopic HCVc-1b in both the cytoplasm and nucleus, which demonstrated their spatial interaction with naturally translocated HCVc174 after HCVc biogenesis. Such colocalization, however, shifted to the cytoplasm in cells with replicating virus of 1b or 2a genotype, indicating that active viral replication confined these interacting proteins in the cytoplasm. Collectively, our findings suggest that spatial interactions of hnRNPH1, NF45, and C14orf166 with HCVc174 likely modulate HCV or cellular functions during acute and chronic HCV infection.


Assuntos
Hepacivirus/metabolismo , Hepatite C/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/metabolismo , Proteína do Fator Nuclear 45/metabolismo , Transativadores/metabolismo , Proteínas do Core Viral/química , Cromatografia Líquida/métodos , Regulação Viral da Expressão Gênica , Genótipo , Células HEK293 , Humanos , Espectrometria de Massas/métodos , Microscopia Confocal/métodos , Plasmídeos/metabolismo , Replicação Viral
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