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1.
Proc Natl Acad Sci U S A ; 118(13)2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33753481

RESUMO

The CXC chemokine receptor type 4 (CXCR4) receptor and its ligand, CXCL12, are overexpressed in various cancers and mediate tumor progression and hypoxia-mediated resistance to cancer therapy. While CXCR4 antagonists have potential anticancer effects when combined with conventional anticancer drugs, their poor potency against CXCL12/CXCR4 downstream signaling pathways and systemic toxicity had precluded clinical application. Herein, BPRCX807, known as a safe, selective, and potent CXCR4 antagonist, has been designed and experimentally realized. In in vitro and in vivo hepatocellular carcinoma mouse models it can significantly suppress primary tumor growth, prevent distant metastasis/cell migration, reduce angiogenesis, and normalize the immunosuppressive tumor microenvironment by reducing tumor-associated macrophages (TAMs) infiltration, reprogramming TAMs toward an immunostimulatory phenotype and promoting cytotoxic T cell infiltration into tumor. Although BPRCX807 treatment alone prolongs overall survival as effectively as both marketed sorafenib and anti-PD-1, it could synergize with either of them in combination therapy to further extend life expectancy and suppress distant metastasis more significantly.


Assuntos
Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Receptores CXCR4/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Dietilnitrosamina/administração & dosagem , Dietilnitrosamina/toxicidade , Sinergismo Farmacológico , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/imunologia , Neoplasias Hepáticas Experimentais/patologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Ratos , Receptores CXCR4/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Mol Cell Neurosci ; 67: 46-54, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26048366

RESUMO

Calorie restriction (CR) has been shown to increase lifespan and delay aging phenotypes in many diverse eukaryotic species. In mouse models of Alzheimer's disease (AD), CR has been shown to decrease amyloid-beta and hyperphosphorylated tau levels and preserve cognitive function. Overexpression of human mutant tau protein has been shown to induce deficits in mitochondrial electron transport chain complex I activity. Therefore, experiments were performed to determine the effects of 4-month CR on brain mitochondrial function in Tg4510 mice, which express human P301L tau. Expression of mutant tau led to decreased ADP-stimulated respiratory rates, but not uncoupler-stimulated respiratory rates. The membrane potential was also slightly higher in mitochondria from the P301L tau mice. As shown previously, tau expression decreased mitochondrial complex I activity. The decreased complex I activity, decreased ADP-stimulated respiratory rate, and increased mitochondrial membrane potential occurring in mitochondria from Tg4510 mice were not restored by CR. However, the CR diet did result in a genotype independent decrease in mitochondrial F0F1-ATPase activity. This decrease in F0F1-ATPase activity was not due to lowered levels of the alpha or beta subunits of F0F1-ATPase. The possible mechanisms through which CR reduces the F0F1-ATPase activity in brain mitochondria are discussed.


Assuntos
Doença de Alzheimer/metabolismo , Restrição Calórica , Mitocôndrias/metabolismo , ATPases Translocadoras de Prótons/metabolismo , Proteínas tau/genética , Doença de Alzheimer/genética , Animais , Encéfalo/metabolismo , Respiração Celular , Potencial da Membrana Mitocondrial , Camundongos , Proteínas tau/metabolismo
3.
Artigo em Inglês | MEDLINE | ID: mdl-38500369

RESUMO

Kidney-specific nanocarriers offer a targeted approach to enhance therapeutic efficacy and reduce off-target effects in renal treatments. The nanocarriers can achieve organ or cell specificity via passive targeting and active targeting mechanisms. Passive targeting capitalizes on the unique physiological traits of the kidney, with factors like particle size, charge, shape, and material properties enhancing organ specificity. Active targeting, on the other hand, achieves renal specificity through ligand-receptor interactions, modifying nanocarriers with molecules, peptides, or antibodies for receptor-mediated delivery. Nanotechnology-enabled therapy targets diseased kidney tissue by modulating podocytes and immune cells to reduce inflammation and enhance tissue repair, or by inhibiting myofibroblast differentiation to mitigate renal fibrosis. This review summarizes the current reports of the drug delivery systems that have been tested in vivo, identifies the nanocarriers that may preferentially accumulate in the kidney, and quantitatively compares the efficacy of various cargo-carrier combinations to outline optimal strategies and future research directions. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies.


Assuntos
Nefropatias , Nanopartículas , Humanos , Nanopartículas/uso terapêutico , Nanopartículas/química , Nanotecnologia , Sistemas de Liberação de Medicamentos , Nefropatias/tratamento farmacológico , Ligantes , Portadores de Fármacos/química
4.
ACS Appl Mater Interfaces ; 13(41): 48478-48491, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34633791

RESUMO

Three-dimensional (3D) spheroid culture provides opportunities to model tumor growth closer to its natural context. The collagen network in the extracellular matrix supports autonomic tumor cell proliferation, but its presence and role in tumor spheroids remain unclear. In this research, we developed an in vitro 3D co-culture model in a microwell 3D (µ-well 3D) cell-culture array platform to mimic the tumor microenvironment (TME). The modular setup is used to characterize the paracrine signaling molecules and the role of the intraspheroidal collagen network in cancer drug resistance. The µ-well 3D platform is made up of poly(dimethylsiloxane) that contains 630 round wells for individual spheroid growth. Inside each well, the growth surface measured 500 µm in diameter and was functionalized with the amphiphilic copolymer. HCT-8 colon cancer cells and/or NIH3T3 fibroblasts were seeded in each well and incubated for up to 9 days for TME studies. It was observed that NIH3T3 cells promoted the kinetics of tumor organoid formation. The two types of cells self-organized into core-shell chimeric tumor spheroids (CTSs) with fibroblasts confined to the shell and cancer cells localized to the core. Confocal microscopy analysis indicated that a type-I collagen network developed inside the CTS along with increased TGF-ß1 and α-SMA proteins. The results were correlated with a significantly increased stiffness in 3D co-cultured CTS up to 52 kPa as compared to two-dimensional (2D) co-culture. CTS was more resistant to 5-FU (IC50 = 14.0 ± 3.9 µM) and Regorafenib (IC50 = 49.8 ± 9.9 µM) compared to cells grown under the 2D condition 5-FU (IC50 = 12.2 ± 3.7 µM) and Regorafenib (IC50 = 5.9 ± 1.9 µM). Targeted collagen homeostasis with Sclerotiorin led to damaged collagen structure and disrupted the type-I collagen network within CTS. Such a treatment significantly sensitized collagen-supported CTS to 5-FU (IC50 = 4.4 ± 1.3 µM) and to Regorafenib (IC50 = 0.5 ± 0.2 µM). In summary, the efficient formation of colon cancer CTSs in a µ-well 3D culture platform allows exploration of the desmoplastic TME. The novel role of intratumor collagen quality as a drug sensitization target warrants further investigation.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Esferoides Celulares/metabolismo , Microambiente Tumoral/fisiologia , Animais , Benzopiranos/farmacologia , Técnicas de Cultura de Células em Três Dimensões/métodos , Técnicas de Cocultura/métodos , Colágeno Tipo I/antagonistas & inibidores , Colágeno Tipo I/metabolismo , Neoplasias Colorretais/metabolismo , Fluoruracila/farmacologia , Humanos , Camundongos , Células NIH 3T3 , Compostos de Fenilureia/farmacologia , Poloxâmero/química , Piridinas/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Microambiente Tumoral/efeitos dos fármacos
5.
J Med Chem ; 64(19): 14513-14525, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34558909

RESUMO

Autophagy is upregulated in response to metabolic stress, a hypoxic tumor microenvironment, and therapeutic stress in various cancers and mediates tumor progression and resistance to cancer therapy. Herein, we identified a cinchona alkaloid derivative containing urea (C1), which exhibited potential cytotoxicity and inhibited autophagy in hepatocellular carcinoma (HCC) cells. We showed that C1 not only induced apoptosis but also blocked autophagy in HCC cells, as indicated by the increased expression of LC3-II and p62, inhibition of autophagosome-lysosome fusion, and suppression of the Akt/mTOR/S6k pathway in the HCC cells. Finally, to improve its solubility and efficacy, we encapsulated C1 into PEGylated lipid-poly(lactic-co-glycolic acid) (PLGA) nanoscale drug carriers. Systemic administration of nanoscale C1 significantly suppressed primary tumor growth and prevented distant metastasis while maintaining a desirable safety profile. Our findings demonstrate that C1 combines autophagy modulation and apoptosis induction in a single molecule, making it a promising therapeutic option for HCC.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Alcaloides de Cinchona/farmacologia , Neoplasias Hepáticas/patologia , Ureia/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Microambiente Tumoral/efeitos dos fármacos
6.
Artigo em Inglês | MEDLINE | ID: mdl-30452358

RESUMO

In this paper, we demonstrate the fabrication of contour-mode resonators (CMRs) with Al0.83Sc0.17N as a piezoelectric layer. Moreover, we assess the electromechanical coupling and the maximum achieved quality factor from 150 to 500 MHz. In comparison to pure aluminum nitride (AlN) CMRs, our results show electromechanical coupling coefficients of more than a 2× factor higher at around 200 MHz. The highest quality factor is measured on a CMR operating at 388 MHz and is in excess of 1600. From the characterization of devices operating at different frequencies, material parameters of the Al0.83Sc0.17N are extracted such as the stiffness constant, the relative permittivity, and the piezoelectric constant. In particular, the reported d31 piezoelectric constant is equal to -3.9 pm/V. This represents a 2.25× improvement when compared to pure AlN. Finally, we report the first temperature compensation experimental results for Al0.83Sc0.17N CMRs. Our results show that about 1.5 [Formula: see text] of sputtered oxide, deposited on top of a released resonator, allows near zero temperature coefficient of frequency variation for CMRs operating up to 500 MHz.

7.
Life Sci ; 232: 116651, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31302195

RESUMO

The miR-19 family, including miR-19a, miR-19b-1 and miR-19b-2, arises from two different paralogous clusters miR-17-92 and miR-106a-363. Although it is identified as oncogenic miRNA, the miR-19 family has also been found to play important roles in regulating normal tissue development. The precise control of miR-19 family level is essential for keeping tissue homeostasis and normal development of organisms. Its dysregulation leads to dysplasia, disease and even cancer. Therefore, this review focuses on the roles of miR-19 family in the development and disease of heart, vessels and neurons to estimate the potential value of miR-19 family as diagnostic biomarker or therapeutic target of cardiac, neurological, and vascular diseases.


Assuntos
Vasos Sanguíneos/metabolismo , MicroRNAs/genética , Miocárdio/metabolismo , Neurônios/metabolismo , Biomarcadores/metabolismo , Humanos
8.
Biol Open ; 7(11)2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30177551

RESUMO

Mitochondrial DNA mutations accumulate with age and may play a role in stem cell aging as suggested by the premature aging phenotype of mitochondrial DNA polymerase gamma (POLG) exonuclease-deficient mice. Therefore, E1A immortalized murine embryonic fibroblasts (MEFs) from POLG exonuclease-deficient and wild-type (WT) mice were constructed. Surprisingly, when some E1A immortalized MEF lines were cultured in pyruvate-containing media they slowly became addicted to the pyruvate. The POLG exonuclease-deficient MEFs were more sensitive to several mitochondrial inhibitors and showed increased reactive oxygen species (ROS) production under standard conditions. When cultured in pyruvate-containing media, POLG exonuclease-deficient MEFs showed decreased oxygen consumption compared to controls. Increased AMP-activated protein kinase (AMPK) signaling and decreased mammalian target of rapamycin (mTOR) signaling delayed aging and influenced mitochondrial function. Therefore, the effects of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK activator, or rapamycin, an mTOR inhibitor, on measures of mitochondrial function were determined. Rapamycin treatment transiently increased respiration only in WT MEFs and, under most conditions, increased ATP levels. Short term AICAR treatment transiently increased ROS production and, under most conditions, decreased ATP levels. Chronic AICAR treatment decreased respiration and ROS production in WT MEFs. These results demonstrate the context-dependent effects of AICAR and rapamycin on mitochondrial function.

9.
J Food Prot ; 77(1): 57-66, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24405999

RESUMO

The objectives of this study were to quantify Salmonella counts on retail raw poultry meat in Vietnam and to phenotypically characterize (serovars and antibiotic resistance) the isolates. A total of 300 chicken carcasses were collected from two cities and two provinces in Vietnam. Salmonella counts on the samples were determined according to the most-probable-number (MPN) method of the U.S. Department of Agriculture, Food Safety and Inspection Service (USDA-FSIS). A total of 457 isolates were serotyped and tested for antibiotic susceptibility. Overall, 48.7% of chicken samples were Salmonella positive with a count of 2.0 log MPN per carcass. There were no significant differences (P > 0.05) in log MPN per carcass by the study variables (market type, storage condition, and chicken production system). There was a significant difference (P < 0.05) in Salmonella-positive prevalence by chicken production system. Among the 22 Salmonella serovars identified, Albany was the most frequent (34.1%), followed by Agona (15.5%) and Dabou (8.8%). Resistance to at least one antibiotic was common (i.e., 73.3%), with high resistance to tetracycline (59.1%) and ampicillin (41.6%). Resistance to three antibiotics was the most frequently found multidrug resistance profile (17.7%, n = 81); the profile that was resistant to the highest number of drugs was resistant to nine antibiotics (0.7%, n = 3). Only Salmonella Albany posed phenotypic resistance to ceftriaxone (a drug of choice to treat severe cases of salmonellosis). The data revealed that, whereas Salmonella prevalence on raw poultry was high (48.7%), counts were low, which suggests that the exposure risk to Salmonella is low. However, improper storage of raw chicken meat and cross-contamination may increase Salmonella cell counts and pose a greater risk for infection. These data may be helpful in developing risk assessment models and preventing the transmission of foodborne Salmonella from poultry to humans in Vietnam.


Assuntos
Antibacterianos/farmacologia , Resistência Microbiana a Medicamentos , Contaminação de Alimentos/análise , Manipulação de Alimentos/métodos , Produtos Avícolas/microbiologia , Salmonella/isolamento & purificação , Animais , Galinhas , Contagem de Colônia Microbiana , Relação Dose-Resposta a Droga , Microbiologia de Alimentos , Humanos , Testes de Sensibilidade Microbiana , Prevalência , Salmonella/classificação , Salmonella/efeitos dos fármacos , Intoxicação Alimentar por Salmonella/prevenção & controle , Estados Unidos , Vietnã
10.
J Food Prot ; 75(10): 1851-4, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23043836

RESUMO

This study was conducted to estimate the prevalence of Salmonella on chicken carcasses collected from six regions in Vietnam. A total of 1,000 whole, dressed chicken carcasses were collected from five cities and seven provinces across the six regions in Vietnam. Of these, 900 samples were collected from wet markets and 100 from supermarkets. All samples were analyzed for the presence of Salmonella according to a method recommended by the U. S. Department of Agriculture, Food Safety and Inspection Service. The overall Salmonella prevalence was 45.9%. There was no significant difference (P > 0.05) in Salmonella prevalence by (i) location (Ha Noi city, 51.1%; Hai Phong city, 45.6%; Da Nang and Can Tho cities, 45.5%; Bac Ninh province and Ho Chi Minh city, 44.7%; Dong Nai province, 44.6%; Ha Tinh province, 44.4%; Phu Tho province, 43.8%; Lao Cai province, 43.5%; Kien Giang province, 41.9%; and Lam Dong province, 40.9%), (ii) market type (wet market, 46.2%; supermarket samples, 43.0%), and (iii) storage temperature at retail (ambient storage, 46.4%; chilled storage, 45.1%). Hence, Salmonella presence on poultry meat in Vietnam was not associated with a specific city or province, market type, or storage temperature at retail. Strategies to reduce Salmonella levels on raw poultry in Vietnam should be undertaken to improve the safety of poultry products and reduce the incidence of human salmonellosis from poultry consumption.


Assuntos
Galinhas/microbiologia , Contaminação de Alimentos/análise , Intoxicação Alimentar por Salmonella/prevenção & controle , Salmonella/isolamento & purificação , Animais , Comércio/normas , Qualidade de Produtos para o Consumidor , Humanos , Prevalência , Vietnã/epidemiologia
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