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1.
bioRxiv ; 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38826238

RESUMO

Over 95% of pancreatic ductal adenocarcinomas (PDAC) harbor oncogenic mutations in K-Ras. Upon treatment with K-Ras inhibitors, PDAC cancer cells undergo metabolic reprogramming towards an oxidative phosphorylation-dependent, drug-resistant state. However, direct inhibition of complex I is poorly tolerated in patients due to on-target induction of peripheral neuropathy. In this work, we develop molecular glue degraders against ZBTB11, a C2H2 zinc finger transcription factor that regulates the nuclear transcription of components of the mitoribosome and electron transport chain. Our ZBTB11 degraders leverage the differences in demand for biogenesis of mitochondrial components between human neurons and rapidly-dividing pancreatic cancer cells, to selectively target the K-Ras inhibitor resistant state in PDAC. Combination treatment of both K-Ras inhibitor-resistant cell lines and multidrug resistant patient-derived organoids resulted in superior anti-cancer activity compared to single agent treatment, while sparing hiPSC-derived neurons. Proteomic and stable isotope tracing studies revealed mitoribosome depletion and impairment of the TCA cycle as key events that mediate this response. Together, this work validates ZBTB11 as a vulnerability in K-Ras inhibitor-resistant PDAC and provides a suite of molecular glue degrader tool compounds to investigate its function.

2.
Viruses ; 15(5)2023 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-37243192

RESUMO

The Zika virus (ZIKV), a member of the Flaviviridae family, is considered a major health threat causing multiple cases of microcephaly in newborns and Guillain-Barré syndrome in adults. In this study, we targeted a transient, deep, and hydrophobic pocket of the "super-open" conformation of ZIKV NS2B-NS3 protease to overcome the limitations of the active site pocket. After virtual docking screening of approximately seven million compounds against the novel allosteric site, we selected the top six candidates and assessed them in enzymatic assays. Six candidates inhibited ZIKV NS2B-NS3 protease proteolytic activity at low micromolar concentrations. These six compounds, targeting the selected protease pocket conserved in ZIKV, serve as unique drug candidates and open new opportunities for possible treatment against several flavivirus infections.


Assuntos
Infecção por Zika virus , Zika virus , Recém-Nascido , Humanos , Zika virus/metabolismo , Infecção por Zika virus/tratamento farmacológico , Proteínas não Estruturais Virais/química , Serina Endopeptidases/metabolismo , Peptídeo Hidrolases , Conformação Proteica , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química
3.
Exp Cell Res ; 429(1): 113652, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37209991

RESUMO

Damage associated molecular patterns (DAMPs), including calreticulin (CRT) exposure, high-mobility group box 1 protein (HMGB1) elevation, and ATP release, characterize immunogenic cell death (ICD) and may play a role in cancer immunotherapy. Triple negative breast cancer (TNBC) is an immunogenic subtype of breast cancer with higher lymphocyte infiltration. Here, we found that regorafenib, a multi-target angiokinase inhibitor previously known to suppress STAT3 signaling, induced DAMPs and cell death in TNBC cells. Regorafenib induced the expression of HMGB1 and CRT, and the release of ATP. Regorafenib-induced HMGB1 and CRT were attenuated following STAT3 overexpression. In a 4T1 syngeneic murine model, regorafenib treatment increased HMGB1 and CRT expression in xenografts, and effectively suppressed 4T1 tumor growth. Immunohistochemical staining revealed increased CD4+ and CD8+ tumor-infiltrating T cells in 4T1 xenografts following regorafenib treatment. Regorafenib treatment or programmed death-1 (PD-1) blockade using anti-PD-1 monoclonal antibody reduced lung metastasis of 4T1 cells in immunocompetent mice. While regorafenib increases the proportion of MHC II high expression on dendritic cells in mice with smaller tumors, the combination of regorafenib and PD-1 blockade did not show a synergistic effect on anti-tumor activity. These results suggest that regorafenib induces ICD and suppresses tumor progression in TNBC. It should be carefully evaluated when developing a combination therapy with an anti-PD-1 antibody and a STAT3 inhibitor.


Assuntos
Proteína HMGB1 , Neoplasias de Mama Triplo Negativas , Camundongos , Humanos , Animais , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Proteína HMGB1/farmacologia , Morte Celular , Trifosfato de Adenosina/farmacologia , Linhagem Celular Tumoral
4.
Nat Commun ; 14(1): 1709, 2023 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-36973293

RESUMO

Defining the mechanisms safeguarding cell fate identity in differentiated cells is crucial to improve 1) - our understanding of how differentiation is maintained in healthy tissues or altered in a disease state, and 2) - our ability to use cell fate reprogramming for regenerative purposes. Here, using a genome-wide transcription factor screen followed by validation steps in a variety of reprogramming assays (cardiac, neural and iPSC in fibroblasts and endothelial cells), we identified a set of four transcription factors (ATF7IP, JUNB, SP7, and ZNF207 [AJSZ]) that robustly opposes cell fate reprogramming in both lineage and cell type independent manners. Mechanistically, our integrated multi-omics approach (ChIP, ATAC and RNA-seq) revealed that AJSZ oppose cell fate reprogramming by 1) - maintaining chromatin enriched for reprogramming TF motifs in a closed state and 2) - downregulating genes required for reprogramming. Finally, KD of AJSZ in combination with MGT overexpression, significantly reduced scar size and improved heart function by 50%, as compared to MGT alone post-myocardial infarction. Collectively, our study suggests that inhibition of barrier to reprogramming mechanisms represents a promising therapeutic avenue to improve adult organ function post-injury.


Assuntos
Células-Tronco Pluripotentes Induzidas , Fatores de Transcrição , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Reprogramação Celular/genética , Células Endoteliais/metabolismo , Diferenciação Celular/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Fibroblastos/metabolismo
5.
Mol Med ; 28(1): 93, 2022 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-35941532

RESUMO

BACKGROUND: Diffuse large B cell lymphoma (DLBCL) is an aggressive and molecularly heterogeneous non-Hodgkin's lymphoma. The B cell receptor (BCR) signaling pathway in DLBCL emerges as a new drug target. Protein phosphatase SHP-1 negatively regulates several oncogenic tyrosine kinases and plays a tumor suppressive role. METHODS: The direct SHP-1 agonists were used to evaluate the potential therapeutic implication of SHP-1 in DLBCL. Immunohistochemical staining for SHP-1 was quantified by H-score. The SHP-1 phosphatase activity was determined using tyrosine phosphatase assay. In vitro studies, including MTT, western blot analysis and cell apoptosis, were utilized to examined biological functions of SHP-1. RESULTS: Oral administration of SHP-1 agonist showed the potent anti-tumor effects compared to a selective Bruton's tyrosine kinase (BTK) inhibitor ibrutinib in mice bearing U2932 xenografts. SHP-1 agonist increased SHP-1 activity as well as downregulated p-Lyn in vivo. Here, we demonstrated that immunohistochemical staining for SHP-1 expression was positive in 76% of DLBCL samples. SHP-1 agonist exerted anti-proliferative and apoptotic effects compared with ibrutinib in DLBCL cells. Mechanistically, SHP-1 agonist decreased BCR signaling, especially p-Lyn, and led to apoptosis. CONCLUSIONS: These data suggest that SHP-1 negatively regulates phosphorylation of Lyn, and targeting SHP-1/p-Lyn using SHP-1 agonist has therapeutic potential for treatment of DLBCL.


Assuntos
Linfoma Difuso de Grandes Células B , Animais , Linhagem Celular Tumoral , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Proteína Tirosina Fosfatase não Receptora Tipo 6 , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais , Tirosina/farmacologia , Tirosina/uso terapêutico , Quinases da Família src/metabolismo
6.
Cell Rep ; 39(2): 110655, 2022 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-35417697

RESUMO

Zika virus (ZIKV) and dengue virus (DENV) are arthropod-borne pathogenic flaviviruses that co-circulate in many countries. To understand some of the pressures that influence ZIKV evolution, we mimic the natural transmission cycle by repeating serial passaging of ZIKV through cultured mosquito cells and either DENV-naive or DENV-immune mice. Compared with wild-type ZIKV, the strains passaged under both conditions exhibit increased pathogenesis in DENV-immune mice. Application of reverse genetics identifies an isoleucine-to-valine mutation (I39V) in the NS2B proteins of both passaged strains that confers enhanced fitness and escape from pre-existing DENV immunity. Introduction of I39V or I39T, a naturally occurring homologous mutation detected in recent ZIKV isolates, increases the replication of wild-type ZIKV in human neuronal precursor cells and laboratory-raised mosquitoes. Our data indicate that ZIKV strains with enhanced transmissibility and pathogenicity can emerge in DENV-naive or -immune settings, and that NS2B-I39 mutants may represent ZIKV variants of interest.


Assuntos
Vírus da Dengue , Dengue , Infecção por Zika virus , Zika virus , Animais , Anticorpos Antivirais , Reações Cruzadas , Vírus da Dengue/genética , Camundongos , Mutação/genética , Zika virus/genética
7.
J Virol ; 95(22): e0099621, 2021 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-34468177

RESUMO

Zika virus (ZIKV) is a mosquito-borne pathogen classified by the World Health Organization (WHO) as a public health emergency of international concern in 2016, and it is still identified as a priority disease. Although most infected individuals are asymptomatic or show mild symptoms, a risk of neurologic complications is associated with infection in adults. Additionally, infection during pregnancy is directly linked to microcephaly and other congenital malformations. Since there are no currently available vaccines or approved therapeutics for this virus, there is a critical unmet need in developing treatments to prevent future ZIKV outbreaks. Toward this end, we performed a large-scale cell-based high-content screen of 51,520 chemical compounds to identify potential antiviral drug candidates. The compound (2E)-N-benzyl-3-(4-butoxyphenyl)prop-2-enamide (SBI-0090799) was found to inhibit replication of multiple ZIKV strains and in different cell systems. SBI-0090799 did not affect viral entry or RNA translation but suppressed RNA replication by preventing the formation of the membranous replication compartment. Selection of drug-resistant viruses identified single-amino-acid substitutions in the N-terminal region of nonstructural protein NS4A, arguing this is the likely drug target. These resistance mutations rescued viral RNA replication and restored the formation of the membranous replication compartment. This mechanism of action is similar to clinically approved NS5A inhibitors for hepatitis C virus (HCV). Taken together, SBI-0090799 represents a promising lead candidate for the development of an antiviral treatment against ZIKV infection for the mitigation of severe complications and potential resurgent outbreaks of the virus. IMPORTANCE This study describes the elucidation of (2E)-N-benzyl-3-(4-butoxyphenyl)prop-2-enamide (SBI-0090799) as a selective and potent inhibitor of Zika virus (ZIKV) replication using a high-throughput screening approach. Mapping and resistance studies, supported by electron microscopy observations, indicate that the small molecule is functioning through inhibition of NS4A-mediated formation of ZIKV replication compartments in the endoplasmic reticulum (ER). Intriguingly, this defines a novel nonenzymatic target and chemical matter for the development of a new class of ZIKV antivirals. Moreover, chemical modulation affecting this nonstructural protein mirrors the identification and development of hepatitis C virus (HCV) NS5A inhibitor daclatasvir and its derivatives, similarly interfering with the formation of the viral replication compartment and also targeting a protein with no enzymatic activity, which have been part of a curative strategy for HCV.


Assuntos
Antivirais/farmacologia , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Replicação Viral/efeitos dos fármacos , Infecção por Zika virus/tratamento farmacológico , Zika virus/efeitos dos fármacos , Animais , Astrócitos , Chlorocebus aethiops , Células Dendríticas , Células HEK293 , Humanos , Cultura Primária de Células , Células Vero , Compartimentos de Replicação Viral/efeitos dos fármacos
8.
Sci Rep ; 11(1): 12171, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108545

RESUMO

Glycoprotein non-metastatic B (GPNMB) is a transmembrane protein overexpressed in numerous cancers including triple-negative breast cancers (TNBC). It has been linked to promote cancer aggressiveness and implicated as a novel target for GPNMB-expressing cancers. In current study, we aimed to explore the clinical significance of GPNMB in TNBC. Among 759 specimens, immunohistochemistry (IHC) exhibited GPNMB expressions were variable in different subtypes and significantly higher in TNBC. Kaplan-Meier analysis revealed GPNMB overexpression in TNBC was associated with worse prognosis especially distant metastasis (P = 0.020, HR = 2.515, CI 1.154-5.480). Multivariate analysis showed GPNMB expression was an independent prognostic factor in terms of recurrence and distant metastasis (P = 0.008, HR = 3.22, CI 1.36-7.61; P = 0.017, HR = 3.08, CI 1.22-7.74). In silico analysis showed high mRNA expression of GPNMB was associated with distant metastasis and GPNMB was overexpressed in TNBC. Furthermore, GPNMB positively correlated with epithelial-mesenchymal transition (EMT) regulators, mesenchymal marker vimentin, MMP and integrins. The protein levels of Twist and MMP2 were upregulated by GPNMB overexpression in TNBC cells. GPNMB-enhanced cell invasion was attenuated by broad spectrum MMP inhibitor (GM 6001) and the selective inhibitor of MMP-2 (ARP100). In summary, GPNMB expression is prevalent in TNBC and may be implicated as a prognostic biomarker in patients with TNBC.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Glicoproteínas de Membrana/metabolismo , Recidiva Local de Neoplasia/patologia , Neoplasias de Mama Triplo Negativas/patologia , Idoso , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Transição Epitelial-Mesenquimal , Humanos , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/cirurgia , Células Tumorais Cultivadas
9.
PLoS One ; 16(1): e0241157, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33406123

RESUMO

We previously reported that IF7 peptide, which binds to the annexin A1 (ANXA1) N-terminus, functions as a tumor vasculature-targeted drug delivery vehicle after intravenous injection. To enhance IF7 stability in vivo, we undertook mirror-image peptide phage display using a synthetic D-peptide representing the ANXA1 N-terminus as target. We then identified peptide sequences, synthesized them as D-amino acids, and designated the resulting peptide dTIT7, which we showed bound to the ANXA1 N-terminus. Whole body imaging of mouse brain tumor models injected with near infrared fluorescent IRDye-conjugated dTIT7 showed fluorescent signals in brain and kidney. Furthermore, orally-administered dTIT7/geldanamycin (GA) conjugates suppressed brain tumor growth. Ours is a proof-of-concept experiment showing that ANXA1-binding D-peptide can be developed as an orally-administrable tumor vasculature-targeted therapeutic.


Assuntos
Anexina A1/antagonistas & inibidores , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Proteínas de Neoplasias/antagonistas & inibidores , Neovascularização Patológica/tratamento farmacológico , Peptídeos , Administração Oral , Animais , Anexina A1/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Peptídeos/síntese química , Peptídeos/química , Peptídeos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
J Pain Symptom Manage ; 61(2): 323-330, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32739560

RESUMO

CONTEXT: The impact of hospice care services on the utilization of life-sustaining treatments during end-of-life care in terminally ill patients has not been extensively studied. OBJECTIVES: To determine the impact of hospice care services on the utilization of life-sustaining treatments during the last three months of life among patients with cancer. METHODS: This nationwide population-based cohort study identified adults with cancer diagnosis from the Taiwan Registry for Catastrophic Illness, 2006-2016. Life-sustaining treatments included cardiopulmonary resuscitation, intubation, mechanical ventilation support, nasogastric tube feeding, and total parenteral nutrition. Hospice care services consisted of hospice inpatient care, hospice-shared care, and hospice home care. The association of hospice care services with the utilization of life-sustaining treatments was determined using multiple logistic regression. RESULTS: Of 516,409 patients with cancer, 310,722 (60.2%) patients used life-sustaining treatments during the last three months of life. After adjusting for covariates, patients with hospice care services were less likely to receive life-sustaining treatments during the last three months of life than those without the services (adjusted odds ratio [AOR]: 0.70; 95% CI: 0.69-0.71). While type of life-sustaining treatments were considered, hospice care services were associated with a lower likelihood of receiving cardiopulmonary resuscitation (AOR: 0.125; 95% CI: 0.118-0.131), endotracheal intubation (AOR: 0.204; 95% CI: 0.199-0.210), mechanical ventilation support (AOR: 0.265; 95% CI: 0.260-0.270), nasogastric tube feeding (AOR: 0.736; 95% CI: 0.727-0.744), and total parenteral nutrition (AOR: 0.86; 95% CI: 0.84-0.88). CONCLUSION: Hospice care services were associated with a lower likelihood of receiving life-sustaining treatments during the last three months of life in patients with cancer.


Assuntos
Cuidados Paliativos na Terminalidade da Vida , Neoplasias , Assistência Terminal , Adulto , Estudos de Coortes , Humanos , Neoplasias/terapia , Taiwan
11.
Br J Cancer ; 123(11): 1633-1643, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32921792

RESUMO

BACKGROUND: Annexin A1 is expressed specifically on the tumour vasculature surface. Intravenously injected IF7 targets tumour vasculature via annexin A1. We tested the hypothesis that IF7 overcomes the blood-brain barrier and that the intravenously injected IF7C(RR)-SN38 eradicates brain tumours in the mouse. METHODS: (1) A dual-tumour model was generated by inoculating luciferase-expressing melanoma B16 cell line, B16-Luc, into the brain and under the skin of syngeneic C57BL/6 mice. IF7C(RR)-SN38 was injected intravenously daily at 7.0 µmoles/kg and growth of tumours was assessed by chemiluminescence using an IVIS imager. A similar dual-tumour model was generated with the C6-Luc line in immunocompromised SCID mice. (2) IF7C(RR)-SN38 formulated with 10% Solutol HS15 was injected intravenously daily at 2.5 µmoles/kg into two brain tumour mouse models: B16-Luc cells in C57BL/6 mice, and C6-Luc cells in nude mice. RESULTS: (1) Daily IF7C(RR)-SN38 injection suppressed tumour growth regardless of cell lines or mouse strains. (2) Daily injection of Solutol-formulated IF7C(RR)-SN38 led into complete disappearance of B16-Luc brain tumour in C57BL/6 mice, whereas this did not occur in C6-Luc in nude mice. CONCLUSIONS: IF7C(RR)-SN38 crosses the blood-brain barrier and suppresses growth of brain tumours in mouse models. Solutol HS15-formulated IF7C(RR)-SN38 may have promoted an antitumour immune response.


Assuntos
Anexina A1/metabolismo , Antineoplásicos/farmacologia , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas , Portadores de Fármacos/farmacologia , Animais , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Peptídeos , Ratos
12.
EBioMedicine ; 54: 102717, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32268268

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) is aggressive and has a poor prognosis. Kynurenine 3-monooxygenase (KMO), a crucial kynurenine metabolic enzyme, is involved in inflammation, immune response and tumorigenesis. We aimed to study the role of KMO in TNBC. METHODS: KMO alteration and expression data from public databases were analyzed. KMO expression levels in TNBC samples were analyzed using immunohistochemistry. Knockdown of KMO in TNBC cells was achieved by RNAi and CRISPR/Cas9. KMO functions were examined by MTT, colony-forming, transwell migration/invasion, and mammosphere assays. The molecular events were analyzed by cDNA microarrays, Western blot, quantitative real-time PCR and luciferase reporter assays. Tumor growth and metastasis were detected by orthotopic xenograft and tail vein metastasis mouse models, respectively. FINDINGS: KMO was amplified and associated with worse survival in breast cancer patients. KMO expression levels were higher in TNBC tumors compared to adjacent normal mammary tissues. In vitro ectopic KMO expression increased cell growth, colony and mammosphere formation, migration, invasion as well as mesenchymal marker expression levels in TNBC cells. In addition, KMO increased pluripotent gene expression levels and promoter activities in vitro. Mechanistically, KMO was associated with ß-catenin and prevented ß-catenin degradation, thereby enhancing the transcription of pluripotent genes. KMO knockdown suppressed tumor growth and the expression levels of ß-catenin, CD44 and Nanog. Furthermore, mutant KMO (known with suppressed enzymatic activity) could still promote TNBC cell migration/invasion. Importantly, mice bearing CRISPR KMO-knockdown TNBC tumors showed decreased lung metastasis and prolonged survival. INTERPRETATION: KMO regulates pluripotent genes via ß-catenin and plays an oncogenic role in TNBC progression.


Assuntos
Regulação Neoplásica da Expressão Gênica , Quinurenina 3-Mono-Oxigenase/metabolismo , Neoplasias de Mama Triplo Negativas/genética , beta Catenina/metabolismo , Animais , Linhagem Celular Tumoral , Células Cultivadas , Feminino , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Quinurenina 3-Mono-Oxigenase/genética , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteína Homeobox Nanog/genética , Proteína Homeobox Nanog/metabolismo , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Regulação para Cima , beta Catenina/genética
13.
Biomed Res Int ; 2020: 1704879, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32090069

RESUMO

BACKGROUND: Late onset depression (LOD) often occurs in the context of vascular disease and may be associated with risk of dementia. Aspirin is widely used to reduce the risk of cardiovascular disease and stroke. However, its role in patients with LOD and risk of dementia remains inconclusive. Materials and Methods. A population-based study was conducted using data from National Health Insurance of Taiwan during 1996-2009. Patients fulfil diagnostic criteria for LOD with or without subsequent dementia (incident dementia) and among whom users of aspirin (75 mg daily for at least 6 months) were identified. The time-dependent Cox proportional hazards model was applied for multivariate analyses. Propensity scores with the one-to-one nearest-neighbor matching model were used to select matching patients. Cumulative incidence of incident dementia after diagnosis of LOD was calculated by Kaplan-Meier Method. RESULTS: A total of 6028 (13.4%) and 40,411 (86.6%) patients were defined as, with and without diagnosis of LOD, among whom 2,424 (41.9%) were aspirin users. Patients with LOD had more comorbidities such as cardiovascular diseases, diabetes, and hypertension comparing to those without LOD. Among patients with LOD, aspirin users had lower incidence of subsequent incident dementia than non-users (Hazard Ratio = 0.734, 95% CI 0.641-0.841, p < 0.001). After matching aspirin users with non-users by propensity scores-matching method, the cumulative incidence of incident dementia was significantly lower in aspirin users of LOD patients (p < 0.001). After matching aspirin users with non-users by propensity scores-matching method, the cumulative incidence of incident dementia was significantly lower in aspirin users of LOD patients (. CONCLUSIONS: Aspirin may be associated with a lower risk of incident dementia in patients with LOD. This beneficial effect of aspirin in LOD patients needs validation in prospective clinical trials and our results should be interpreted with caution.


Assuntos
Aspirina/uso terapêutico , Demência/tratamento farmacológico , Demência/epidemiologia , Depressão/complicações , Idade de Início , Idoso , Estudos de Coortes , Demência/etiologia , Feminino , Humanos , Incidência , Masculino , Pontuação de Propensão , Fatores de Risco
14.
Front Pharmacol ; 11: 597703, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33568997

RESUMO

Rhizoma Coptidis is a popular phytomedicine for the treatment of type 2 diabetes in Asia, but its effective dose for diabetes treatment remains confused because of diverse origins. This study aimed to investigate the dose-response effects of Rhizoma Coptidis extract granules (RCEG), produced with standardized quality control, on hypoglycemic effects in patients with type 2 diabetes. We conducted a retrospective analysis of Chang Gung Research Database from January 01, 2008 to November 30, 2017. Outpatients visiting traditional Chinese medicine clinics and receiving RCEG for type 2 diabetes treatment were included. Plasma glucose, lipid, and other parameters were analyzed from 93 patients with a total of 737 visits within 60 weeks. Scatter plots with the LOESS analysis were used to explore the association between RCEG dose and hypoglycemic effect. The minimal effective dose was chosen to divide the study population into the high-dose and low-dose RCEG groups. Non-parametric tests were used for between-group and within-group comparisons. The multivariate nonlinear mixed-effects model was applied to access the effect of treatment length and groups simultaneously on the change of HbA1c and fasting plasma glucose. The "arule" package in R was used to present the network diagram of RCEG and other co-prescriptions. We first discovered a significant relationship between RCEG dose and HbA1c reduction when the dose reached 0.08 g/kg/day or higher. We thus defined 0.08 g/kg/day of RCEG as the minimum effective dose, and a threshold to separate patients into the high-dose (≥0.08 g/kg/d) and low-dose (<0.08 g/kg/d) RCEG groups. In the high-dose RCEG group, a significant decrease in total cholesterol and a trend toward triglyceride reduction were also noted. Patients more effectively responded to RCEG treatment if they had a higher initial HbA1c level, higher heart rates, better liver function tests, and better tolerance to the higher dose and treatment duration of RCEG. In addition, digestive/tonic/dampness draining formulas and blood regulation recipes were two of the most frequent co-prescriptions with RCEG. This study concluded that RCEG at a dose exceeding 0.08 g/kg/d had beneficial effects on glycemic and lipid control, without showing nephro- or hepatotoxicity, in patients with type 2 diabetes.

15.
Elife ; 82019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31637999

RESUMO

High-content phenotypic screening has become the approach of choice for drug discovery due to its ability to extract drug-specific multi-layered data. In the field of epigenetics, such screening methods have suffered from a lack of tools sensitive to selective epigenetic perturbations. Here we describe a novel approach, Microscopic Imaging of Epigenetic Landscapes (MIEL), which captures the nuclear staining patterns of epigenetic marks and employs machine learning to accurately distinguish between such patterns. We validated the MIEL platform across multiple cells lines and using dose-response curves, to insure the fidelity and robustness of this approach for high content high throughput drug discovery. Focusing on noncytotoxic glioblastoma treatments, we demonstrated that MIEL can identify and classify epigenetically active drugs. Furthermore, we show MIEL was able to accurately rank candidate drugs by their ability to produce desired epigenetic alterations consistent with increased sensitivity to chemotherapeutic agents or with induction of glioblastoma differentiation.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Descoberta de Drogas/métodos , Epigênese Genética/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Histonas/genética , Proteínas de Neoplasias/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/genética , Núcleo Celular/metabolismo , Relação Dose-Resposta a Droga , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Histonas/metabolismo , Humanos , Processamento de Imagem Assistida por Computador/estatística & dados numéricos , Aprendizado de Máquina , Microscopia de Fluorescência , Proteínas de Neoplasias/metabolismo
16.
PLoS One ; 14(8): e0221199, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31415655

RESUMO

BACKGROUND: In Asian countries, many patients with type 2 diabetes fail to achieve controlled glycated hemoglobin (HbA1c) levels while taking several classes of oral hypoglycemic agents (OHAs). Traditional Chinese medicine could be an alternative therapeutic option for poorly controlled type 2 diabetes. YH1 is a concentrated Chinese herbal extract formula that combines Rhizoma Coptidis and Shen-Ling-Bai-Zhu-San. This randomized, double-blind, placebo-controlled pilot study evaluated YH1 as an add-on medication for poorly controlled type 2 diabetes. METHODS: Forty-six patients with poorly controlled type 2 diabetes were randomly assigned 1:1 to the YH1 or placebo group. Before the trial, all subjects had received three or more classes of OHAs with HbA1c > 7.0% (53 mmol/mol) and a body mass index ≥ 23 kg/m2. During the 12-week trial, participants continued to take OHAs without any dose or medication changes. The primary endpoint was the percentage change in HbA1c level. Per-protocol analysis was applied to the final evaluation. RESULTS: At week 12, there was an 11.1% reduction in HbA1c from baseline and a 68.9% increase in homeostatic model assessment (HOMA) of ß cell function in the YH1 group, which also exhibited significant reductions in two-hour postprandial glucose (-26.2%), triglycerides (-29.5%), total cholesterol (-21.6%), low-density lipoprotein cholesterol (-17.4%), body weight (-0.5%), and waist circumference (-1.1%). The changes in fasting plasma glucose, HOMA insulin resistance and symptom scores were not significantly different between the YH1 and placebo groups. No serious adverse events occurred during this clinical trial. CONCLUSIONS: This pilot study indicates that YH1 together with OHAs can improve hypoglycemic action and ß-cell function in overweight/obese patients with poorly controlled type 2 diabetes. YH1 is a safe add-on medication for OHAs and has beneficial effects on weight control and lipid metabolism. A larger study population with longer treatment and follow-up periods is required for further verification.


Assuntos
Araceae/química , Diabetes Mellitus Tipo 2 , Medicamentos de Ervas Chinesas/administração & dosagem , Obesidade , Extratos Vegetais/administração & dosagem , Plantas Medicinais/química , Adulto , Idoso , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Método Duplo-Cego , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/tratamento farmacológico , Projetos Piloto , Extratos Vegetais/química
17.
EBioMedicine ; 40: 263-275, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30651219

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) remains difficult to be targeted. SET and cancerous inhibitor of protein phosphatase 2A (CIP2A) are intrinsic protein-interacting inhibitors of protein phosphatase 2A (PP2A) and frequently overexpressed in cancers, whereas reactivating PP2A activity has been postulated as an anti-cancer strategy. Here we explored this strategy in TNBC. METHODS: Data from The Cancer Genome Atlas (TCGA) database was analyzed. TNBC cell lines were used for in vitro studies. Cell viability was examined by MTT assay. The apoptotic cells were examined by flow cytometry and Western blot. A SET-PP2A protein-protein interaction antagonist TD19 was used to disrupt signal transduction. In vivo efficacy of TD19 was tested in MDA-MB-468-xenografted animal model. FINDINGS: TCGA data revealed upregulation of SET and CIP2A and positive correlation of these two gene expressions in TNBC tumors. Ectopic SET or CIP2A increased cell viability, migration, and invasion of TNBC cells. Notably ERK inhibition increased PP2A activity. ERK activation is known crucial for Elk-1 activity, a transcriptional factor regulating CIP2A expression, we hypothesized an oncogenic feedforward loop consisting of pERK/pElk-1/CIP2A/PP2A. This loop was validated by knockdown of PP2A and ectopic expression of Elk-1, showing reciprocal changes in loop members. In addition, ectopic expression of SET increased pAkt, pERK, pElk-1 and CIP2A expressions, suggesting a positive linkage between SET and CIP2A signaling. Moreover, TD19 disrupted this CIP2A-feedforward loop by restoring PP2A activity, demonstrating in vitro and in vivo anti-cancer activity. Mechanistically, TD19 downregulated CIP2A mRNA via inhibiting pERK-mediated Elk-1 nuclear translocation thereby decreased Elk-1 binding to the CIP2A promoter. INTERPRETATION: These findings suggested that a novel oncogenic CIP2A-feedforward loop contributes to TNBC progression and targeting SET to disrupt this oncogenic CIP2A loop showed therapeutic potential in TNBC.


Assuntos
Autoantígenos/metabolismo , Chaperonas de Histonas/metabolismo , Proteínas de Membrana/metabolismo , Proteína Fosfatase 2/metabolismo , Fatores de Transcrição/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autoantígenos/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Proteínas de Ligação a DNA , Modelos Animais de Doenças , Cloridrato de Erlotinib/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana/genética , Camundongos , Modelos Biológicos , Regiões Promotoras Genéticas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Cancers (Basel) ; 11(1)2019 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-30658422

RESUMO

Triple-negative breast cancer (TNBC) is a complex disease associated with the aggressive phenotype and poor prognosis. TNBC harbors heterogeneous molecular subtypes with no approved specific targeted therapy. It has been reported that HER receptors are overexpressed in breast cancer including TNBC. In this study, we evaluated the efficacy of varlitinib, a reversible small molecule pan-HER inhibitor in TNBC. Our results showed that varlitinib reduced cell viability and induced cell apoptosis in most TNBC cell lines but not in MDA-MB-231 cells. MEK and ERK inhibition overcame resistance to varlitinib in MDA-MB-231 cells. Varlitinib inhibited HER signaling which led to inhibition of migration, invasion and mammosphere formation of TNBC cells as well as significant suppression of tumor growth of MDA-MB-468 xenograft mouse model. In summary, these results suggest that HER signaling plays an important role in TNBC progression and that pan-HER inhibition is potentially an effective treatment for TNBC patients.

19.
J Clin Med ; 7(9)2018 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-30154367

RESUMO

Adjuvant tamoxifen reduces the recurrence rate of estrogen receptor (ER)-positive breast cancer. Previous in vitro studies have suggested that tamoxifen can affect the cancerous inhibitor of protein phosphatase 2A (CIP2A)/protein phosphatase 2A (PP2A)/phosphorylation Akt (pAkt) signaling in ER-negative breast cancer cells. In addition to CIP2A, SET nuclear proto-oncogene (SET) oncoprotein is another intrinsic inhibitor of PP2A, participating in cancer progression. In the current study, we explored the clinical significance of SET, CIP2A, PP2A, and Akt in patients with ER-positive breast cancer receiving adjuvant tamoxifen. A total of 218 primary breast cancer patients receiving adjuvant tamoxifen with a median follow-up of 106 months were analyzed, of which 17 (7.8%) experienced recurrence or metastasis. In an immunohistochemical (IHC) stain, SET overexpression was independently associated with worse recurrence-free survival (RFS) (hazard ratio = 3.72, 95% confidence interval 1.26⁻10.94, p = 0.017). In silico analysis revealed mRNA expressions of SET, PPP2CA, and AKT1 significantly correlated with worse RFS. In vitro, SET overexpression reduced tamoxifen-induced antitumor effects and drove luciferase activity in an Estrogen receptor element (ERE)-dependent manner. In conclusion, SET is a prognostic biomarker in patients with primary ER-positive breast cancer receiving adjuvant tamoxifen and may contribute to the failure of the tamoxifen treatment by modulating the ER signaling. Our study warrants further investigation into the potential role of SET in ER-positive breast cancer.

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