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BACKGROUND: Patients with diabetes mellitus are at higher risk of myocardial ischemia/ reperfusion injury (MI/RI). Shuxin decoction (SXT) is a proven recipe modi-fication from the classic herbal formula "Wu-tou-chi-shi-zhi-wan" according to the traditional Chinese medicine theory. It has been successfully used to alleviate secondary MI/RI in patients with diabetes mellitus in the clinical setting. However, the underlying mechanism is still unclear. AIM: To further determine the mechanism of SXT in attenuating MI/RI associated with diabetes. METHODS: This paper presents an ensemble model combining network pharmacology and biology. The Traditional Chinese Medicine System Pharmacology Database was accessed to select key components and potential targets of the SXT. In parallel, therapeutic targets associated with MI/RI in patients with diabetes were screened from various databases including Gene Expression Omnibus, DisGeNet, Genecards, Drugbank, OMIM, and PharmGKB. The potential targets of SXT and the therapeutic targets related to MI/RI in patients with diabetes were intersected and subjected to bioinformatics analysis using the Database for Annotation, Visualization and Integrated Discovery. The major results of bioinformatics analysis were subsequently validated by animal experiments. RESULTS: According to the hypothesis derived from bioinformatics analysis, SXT could possibly ameliorate lipid metabolism disorders and exert anti-apoptotic effects in MI/RI associated with diabetes by reducing oxidized low density lipoprotein (LDL) and inhibiting the advanced glycation end products (AGE)-receptor for AGE (RAGE) signaling pathway. Subsequent animal experiments confirmed the hypothesis. The treatment with a dose of SXT (2.8 g/kg/d) resulted in a reduction in oxidized LDL, AGEs, and RAGE, and regulated the level of blood lipids. Besides, the expression of apoptosis-related proteins such as Bax and cleaved caspase 3 was down-regulated, whereas Bcl-2 expression was up-regulated. The findings indicated that SXT could inhibit myocardial apoptosis and improve cardiac function in MI/RI in diabetic rats. CONCLUSION: This study indicated the active components and underlying molecular therapeutic mechanisms of SXT in MI/RI with diabetes. Moreover, animal experiments verified that SXT could regulate the level of blood lipids, alleviate cardiomyocyte apoptosis, and improve cardiac function through the AGE-RAGE signaling pathway.
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BACKGROUND: Ultrasonography is the most widely used technique to diagnose echinococcosis; however, challenges in using this technique and the demand on medical resources, especially in low-income or remote areas, can delay diagnosis. We aimed to develop a deep convolutional neural network (DCNN) model based on ultrasonography to identify echinococcosis and its types, especially alveolar echinococcosis. METHODS: This retrospective, large-scale, multicentre study used ultrasound images from patients assessed at 84 hospitals in China, obtained between Jan 1, 2002, and Dec 31, 2021. Patients with a diagnosis of cystic echinococcosis, alveolar echinococcosis, or seven other types of focal liver lesions were included. We tested ResNet-50, ResNext-50, and VGG-16 as the backbone network architecture for a classification DCNN model and input the perinodular information from the ultrasound images. We trained and validated the DCNN model to diagnose and classify echinococcosis using still greyscale ultrasound images of focal liver lesions in four stages: differentiating between echinococcosis and other focal liver lesions (stage one); differentiating cystic echinococcosis, alveolar echinococcosis, and other focal liver lesions (stage two); differentiating cystic echinococcosis, alveolar echinococcosis, benign other focal liver lesions, and malignant focal liver lesions (stage three); and differentiating between active and transitional cystic echinococcosis and inactive cystic echinococcosis (stage four). We then tested the algorithm on internal, external, and prospective test datasets. The performance of DCNN was also compared with that of 12 radiologists recruited between Jan 15, 2022, and Jan 28, 2022, from Qinghai, Xinjiang, Anhui, Henan, Xizang, and Beijing, China, with different levels of diagnostic experience for echinococcosis and other focal liver lesions in a subset of ultrasound data that were randomly chosen from the prospective test dataset. The study is registered at ClinicalTrials.gov (NCT03871140). FINDINGS: The study took place between Jan 1, 2002, and Dec 31, 2021. In total, to train and test the DCNN model, we used 9631 liver ultrasound images from 6784 patients (2819 [41·7%] female patients and 3943 [58·3%] male patients) from 87 Chinese hospitals. The DCNN model was trained with 6328 images, internally validated with 984 images, and tested with 2319 images. The ResNet-50 network architecture outperformed VGG-16 and ResNext-50 and was generalisable, with areas under the receiver operating characteristic curve (AUCs) of 0·982 (95% CI 0·960-0·994), 0·984 (0·972-0·992), and 0·913 (0·886-0·935) in distinguishing echinococcosis from other focal liver lesions; 0·986 (0·966-0·996), 0·962 (0·946-0·975), and 0·900 (0·872-0·924) in distinguishing alveolar echinococcosis from cystic echinococcosis and other focal liver lesions; and 0·974 (0·818-1·000), 0·956 (0·875-0·991), and 0·944 (0·844-0·988) in distinguishing active and transitional cystic echinococcosis from inactive echinococcosis in the three test datasets. Specifically, in patients with the hepatitis B or hepatitis C virus, the model could distinguish alveolar echinococcosis from hepatocellular carcinoma with an AUC of 0·892 (0·812-0·946). In identifying echinococcosis, the model showed significantly better performance compared with senior radiologists from a high-endemicity area (AUC 0·942 [0·904-0·967] vs 0·844 [0·820-0·866]; p=0·027) and improved the diagnostic ability of junior, attending, and senior radiologists before and after assistance with AI with comparison of AUCs of 0·743 (0·714-0·770) versus 0·850 (0·826-0·871); p<0·0001, 0·808 (0·782-0·832) versus 0·886 (0·864-0·905); p<0·0001, and 0·844 (0·820-0·866) versus 0·870 (0·847-0·890); p=0·092, respectively. INTERPRETATION: The DCNN model was shown to be accurate and robust, and could improve the ultrasound diagnostic ability of radiologists for echinococcosis and its types for highly endemic and remote regions. FUNDING: National Natural Science Foundation of China and National Key Research & Development Program of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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Equinococose Hepática , Equinococose , Neoplasias Hepáticas , Humanos , Masculino , Feminino , Estudos Retrospectivos , Equinococose Hepática/diagnóstico por imagem , Estudos Prospectivos , Redes Neurais de Computação , Equinococose/diagnóstico por imagem , UltrassonografiaRESUMO
While endocrine therapy is considered as an effective way to treat breast cancer, it still faces many challenges, such as drug resistance and individual discrepancy. Therefore, novel preventive and therapeutic modalities are still in great demand to decrease the incidence and mortality rate of breast cancer. Numerous studies suggested that G protein-coupled estrogen receptor (GPER), a membrane estrogen receptor, is a potential target for breast cancer prevention and treatment. It was also shown that not only endogenous estrogens can activate GPERs, but many phytoestrogens can also function as selective estrogen receptor modulators (SERMs) to interact GPERs. In this review, we discussed the possible mechanisms of GPERs pathways and shed a light of developing novel phytoestrogens based dietary supplements against breast cancers.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/prevenção & controle , Neoplasias da Mama/metabolismo , Fitoestrógenos/farmacologia , Fitoestrógenos/uso terapêutico , Receptores de Estrogênio/metabolismo , Estrogênios/metabolismo , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Suplementos NutricionaisRESUMO
C-C chemokine receptor 5(CCR5) is a cell membrane protein from G protein-coupled receptors (GPCR) family, which is an important modulator for leukocyte activation and mobilization. In the 1980s, several reports suggest that lack of the HIV-1 co-receptor, the chemokine receptor CCR5, offers protection against HIV infection. Later, it was shown that CCR5 was confirmed to be the most common co-receptor for the HIV-1 virus R5 strain. In recent years, many studies have shown that CCR5 is closely related to the development of various cancers and inflammations to facilitate the discovery of CCR5 antagonists. There are many types of CCR5 antagonists, mainly including chemokine derivatives, non-peptide small molecule compounds, monoclonal antibodies, and peptide compounds. This review focus on the recent research processes and pharmacological effects of CCR5 antagonists such as Maraviroc, TAK-779 and PRO 140. After focusing on the therapeutic effect of CCR5 antagonists on AIDS, it also discusses the therapeutic prospect of CCR5 in other diseases such as inflammation and tumor.
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Fármacos Anti-HIV/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/uso terapêutico , Antagonistas dos Receptores CCR5/uso terapêutico , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Animais , Fármacos Anti-HIV/metabolismo , Anti-Inflamatórios/metabolismo , Antineoplásicos/metabolismo , Antagonistas dos Receptores CCR5/metabolismo , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Humanos , Inflamação/tratamento farmacológico , Neoplasias/tratamento farmacológico , Receptores CCR5/metabolismoRESUMO
The rapid development of nanotechnology results in the emergence of nanomedicines, but the effective delivery of drugs to tumor sites remains a great challenge. Prodrug-based cancer nanomedicines thus emerged due to their unique advantages, including high drug load efficiency, reduced side effects, efficient targeting, and real-time controllability. A distinctive characteristic of prodrug-based nanomedicines is that they need to be activated by a stimulus or multi-stimulus to produce an anti-tumor effect. A better understanding of various responsive approaches could allow researchers to perceive the mechanism of prodrug-based nanomedicines effectively and further optimize their design strategy. In this review, we highlight the stimuli-responsive pathway of prodrug-based nanomedicines and their anticancer applications. Furthermore, various types of prodrug-based nanomedicines, recent progress and prospects of stimuli-responsive prodrug-based nanomedicines and patient data in the clinical application are also summarized. Additionally, the current development and future challenges of prodrug-based nanomedicines are discussed. We expect that this review will be valuable for readers to gain a deeper understanding of the structure and development of prodrug-based cancer nanomedicines to design rational and effective drugs for clinical use.
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Nanopartículas/química , Neoplasias/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Humanos , Concentração de Íons de Hidrogênio , Estresse Oxidativo , Pró-Fármacos/químicaRESUMO
Cyclic nucleotide phosphodiesterase 4 (PDE4) specifically hydrolyzes cyclic adenosine monophosphate (cAMP) and plays vital roles in biological processes such as cancer development. To date, PDE4 inhibitors have been widely studied as therapeutics for the treatment of various diseases such as chronic obstructive pulmonary disease, and many of them have progressed to clinical trials or have been approved as drugs. Herein, we review the advances in the development of PDE4 inhibitors in the past decade and will focus on their pharmacophores, PDE4 subfamily selectivity, and therapeutic potential. Hopefully, this analysis will lead to a strategy for development of novel therapeutics targeting PDE4.
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Desenvolvimento de Medicamentos , Inibidores da Fosfodiesterase 4/farmacologia , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Descoberta de Drogas , Humanos , Estrutura Molecular , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/uso terapêutico , Conformação Proteica , Quinolonas/química , Vômito/tratamento farmacológicoRESUMO
Heart failure is a disease with high mortality and the risk of heart failure increases in magnitude with age. The patients of heart failure is increasing year by year. Hence, Pharmaceutical researchers have to develop new drugs with better pharmacological effects to coping with this phenomenon. In this article, we reviewed the small molecule compounds for heart failure that have been marketed in recent years or are promising to enter clinical research. We also reviewed the SAR (structure activity relationship) of these molecules, such as renin inhibitors, ROMK inhibitors, a kind of new diuretics, and some dual-targets inhibitors. These small molecules proven to be beneficial effect on heart failure patients. Which may provide ideas for the design of novel anti-heart failure therapeutic drugs.
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Inibidores Enzimáticos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/uso terapêutico , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Insuficiência Cardíaca/enzimologia , Humanos , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
Joint replacement and bone reconstructive surgeries are on the rise globally. Current strategies for implants and bone regeneration are associated with poor integration and healing resulting in repeated surgeries. A multidisciplinary approach involving basic biological sciences, tissue engineering, regenerative medicine and clinical research is required to overcome this problem. Considering the nanostructured nature of bone, expertise and resources available through recent advancements in nanobiotechnology enable researchers to design and fabricate devices and drug delivery systems at the nanoscale to be more compatible with the bone tissue environment. The focus of this review is to present the recent progress made in the rationale and design of nanomaterials for tissue engineering and drug delivery relevant to bone regeneration.
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Regeneração Óssea/fisiologia , Nanoestruturas/química , Animais , Materiais Biocompatíveis/química , Regeneração Óssea/genética , Osso e Ossos/citologia , Humanos , Nanotecnologia/métodos , Engenharia Tecidual/métodosRESUMO
Biotite, also called black mica (BM), is a group of sheet silicate minerals with great potential in various fields. However, synthesis of high-quality BM nanosheets (NSs) remains a huge challenge. Here, an exfoliation approach is provided that combines calcination, n-butyllithium exchange and intercalation, and liquid exfoliating processes for the high-yield synthesis of ultrathin BM NSs. Due to the presence of MgO, Fe2O3, and FeO in these NSs, PEGylated BM can be engineered as an intelligent theranostic platform with the following unique features: i) Fe3+ can damage the tumor microenvironment (TME) through glutathione consumption and O2 production; ii) Generated O2 can be further catalyzed by MgO with oxygen vacancy to generate ·O2 -; iii) The Fe2+-catalyzed Fenton reaction can produce ·OH by disproportionation reactions of H2O2 in the TME; iv) Reactions in (i) and (iii) circularly regenerate Fe2+ and Fe3+ for continuous consumption of glutathione and H2O2 and constant production of ·OH and O2; v) The NSs can be triggered by a 650 nm laser to generate ·O2 - from O2 as well as by an 808 nm laser to generate local hyperthermia; and vi) The fluorescent, photoacoustic, and photothermal imaging capabilities of the engineered NSs allow for multimodal imaging-guided breast cancer treatment.
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Aurora and polo-like kinases control the G2/M phase in cell mitosis, which are both considered as crucial targets for cancer cell proliferations. Here, naphthalene-based Aurora/PLK coinhibitors as leading compounds were designed through in silico approach, and a total of 36 derivatives were synthesized. One candidate (AAPK-25) was selected under in vitro cell based high throughput screening with an IC50 value = 0.4 µM to human colon cancer cell HCT-116. A kinome scan assay showed that AAPK-25 was remarkably selective to both Aurora and PLK families. The relevant genome pathways were also depicted by microarray based gene expression analysis. Furthermore, validated from a set of in vitro and in vivo studies, AAPK-25 significantly inhibited the development of the colon cancer growth and prolonged the median survival time at the end of the administration (p < 0.05). To sum up, AAPK-25 has a great potential to be developed for a chemotherapeutic agent in clinical use.
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Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Aurora Quinase A/antagonistas & inibidores , Aurora Quinase A/metabolismo , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor , Quinase 1 Polo-LikeRESUMO
Acute myeloid leukemia (AML) is a malignant disease characterized by abnormal growth and differentiation of hematopoietic stem cells. Although the pathogenesis has not been fully elucidated, many specific gene mutations have been found in AML. Fms-like tyrosine kinase 3 (FLT3) is recognized as a drug target for the treatment of AML, and the activation mutations of FLT3 were found in about 30% of AML patients. Targeted inhibition of FLT3 receptor tyrosine kinase has shown promising results in the treatment of FLT3 mutation AML. Unfortunately, the therapeutic effects of FLT3 tyrosine kinase inhibitors used as AML monotherapy are usually accompanied by the high risk of resistance development within a few months after treatment. FLT3 dual inhibitors were generated with the co-inhibition of FLT3 and another target, such as CDK4, JAK2, MEK, Mer, Pim, etc., to solve the problems mentioned above. As a result, the therapeutic effect of the drug is significantly improved, while the toxic and side effects are reduced. Besides, the life quality of AML patients with FLT3 mutation has been effectively improved. In this paper, we reviewed the studies of dual FLT3 inhibitors that have been discovered in recent years for the treatment of AML.
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Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Tirosina Quinase 3 Semelhante a fms/metabolismoRESUMO
Sirtuins family is a class of NDA+ dependent protein deacetylases that play a key role in the regulation of several aspects of biological processes, such as cell cycle regulation, autophagy, immune and inflammatory response. Many studies have shown that sirtuins2 as a key player in the cancer pathway is of great significance in tumorigenesis. This review summarizes the newly discovered, in recent years, some SIRT2 inhibitors for cancer target structure, action mechanism, biological activity, substrate specificity, and signaling pathways.
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Antineoplásicos , Inibidores de Histona Desacetilases , Neoplasias , Sirtuína 2/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Quimioterapia Combinada , Epigênese Genética/efeitos dos fármacos , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/genéticaRESUMO
The emergence of novel two-dimensional (2D) monoelemental materials (Xenes) has shown remarkable potential for their applications in different fields of technology, as well as addressing new discoveries in fundamental science. Xenes (e.g., borophene, silicene, germanene, stanene, phosphorene, arsenene, antimonene, bismuthene, and tellurene) are of particular interest because they are the most chemically tractable materials for synthetic exploration. Owing to their excellent physical, chemical, electronic and optical properties, Xenes have been regarded as promising agents for biosensors, bioimaging, therapeutic delivery, and theranostics, as well as in several other new bio-applications. In this tutorial review, we summarize their general properties including the classification of Xenes according to their bulk properties. The synthetic and modification methods of Xenes are also presented. Furthermore, the representative Xene nanoplatforms for various biomedical applications are highlighted. Finally, research progress, challenges, and perspectives for the future development of Xenes in biomedicines are discussed.
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Materiais Biocompatíveis/química , Nanoestruturas/química , Animais , Materiais Biocompatíveis/uso terapêutico , Técnicas Biossensoriais/métodos , Humanos , Modelos Moleculares , Nanoestruturas/uso terapêutico , Nanoestruturas/ultraestrutura , Nanotecnologia/métodos , Imagem Óptica/métodos , Nanomedicina Teranóstica/métodosRESUMO
Monoclonal antibody (mAb), cytotoxins, and linker technology are three essential elements for developing a successful antibody-drug conjugate (ADC). In the research and development of ADCs industry, selected cytotoxins, such as auristatins and maytansines, are commonly tubulin inhibitors which are widely put into clinical use. Thereafter, with the booming development of ADCs, a large number of pharmaceutical companies have expanded a wide range of selectable cytotoxin product lines as well. Recently, the cytotoxic substance of 7-ethyl-10-hydroxycamptothecin (SN-38) conjugated to the monoclonal antibody by linker technology is developed as the second-generation ADCs. Here, the SN-38 families together with sacituzumab govitecan and labetuzumab govitecan are reviewed, whose features of metabolic pathway and toxicity in vivo are well-known. In sum, these methodology and technology would be convenient and flexible to be applied for developing the novel class of cytotoxins in ADCs industry.
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Imunoconjugados/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Citotoxinas/química , Citotoxinas/uso terapêutico , Humanos , Imunoconjugados/químicaRESUMO
Cisplatin-based chemotherapy is a widely used first-line strategy for numerous cancers. However, drug resistances are often inevitable accompanied by the long-term use of cisplatin in vivo, significantly hampering its therapeutic efficacy and clinical outcomes. Among others, autophagy induction is one of the most common causes of tumor resistance to cisplatin. Herein, a self-assembled nanoprodrug platform was developed with the synergistic effect of cisplatin and RNAi to fight against cisplatin-resistant lung cancer. The nanoprodrug platform consists of three molecular modules, including prodrug complex of Pt(IV)-peptide-bis(pyrene), DSPE-PEG, and cRGD-modified DSPE-PEG. The Pt(IV) is immobilized with peptide via amide bonds, allowing the Pt(IV) to be loaded with a loading efficiency of >95% and rapid-release active platinum ions (Pt(II)) in the presence of glutathione (GSH). Meanwhile, the peptide of the prodrug complex could efficiently deliver Beclin1 siRNA ( Beclin1 is an autophagy initiation factor) to the cytoplasm, thereby leading to autophagy inhibition. In addition, incorporation of DSPE-PEG and cRGD-modified DSPE-PEG molecules improves the biocompatibility and cellular uptake of the nanoprodrug platform. In vivo results also indicate that the nanoprodrug platform significantly inhibits the growth of a cisplatin-resistant tumor on xenograft mice models with a remarkable inhibition rate, up to 84% after intravenous injection.
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Cisplatino/farmacologia , Neoplasias/tratamento farmacológico , Peptídeos/farmacologia , Pró-Fármacos/farmacologia , Animais , Autofagia/efeitos dos fármacos , Proteína Beclina-1/química , Proteína Beclina-1/genética , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Linhagem Celular Tumoral , Cisplatino/efeitos adversos , Cisplatino/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Camundongos , Nanopartículas/química , Neoplasias/genética , Peptídeos/síntese química , Peptídeos/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , RNA Interferente Pequeno/química , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Left ventricular (LV) remodeling remains unknown in patients with acute Type B aortic dissection (aTBAD) after thoracic endovascular aortic repair (TEVAR) during follow-up. METHODS: Between May 2004 and January 2016, 163 consecutive patients (136 males, mean preoperative age: 51.06⯱â¯10.79â¯years) with aTBAD underwent TEVAR. A linear mixed model was used to evaluate risk factor influencing on LV remodeling and investigate longitudinal changes in LV thickness, diameter, volume, function and mass at preoperation, postoperation, short- and mid-term follow-up. RESULTS: Median follow-up time was 48.0â¯months (quartiles 1-3, 31-84â¯months, maximum 147â¯months). LV thickness and mass followed a continuous downward trend over time. Interventricular septal thickness at end-diastole significantly decreased at mid-term follow-up (time, pâ¯<â¯0.001: preoperative 11.59⯱â¯0.14â¯mm vs mid-term 10.82⯱â¯0.15â¯mm, pâ¯<â¯0.001; postoperative 11.40⯱â¯0.14â¯mm vs mid-term 10.82⯱â¯0.15â¯mm, pâ¯=â¯0.006). LV posterior wall thickness at end-diastole was markedly reduced at mid-term follow-up (time, pâ¯<â¯0.001: preoperative 10.89⯱â¯0.11â¯mm vs mid-term 10.02⯱â¯0.11â¯mm, pâ¯<â¯0.001; postoperative 10.78⯱â¯0.13â¯mm vs mid-term 10.02⯱â¯0.11â¯mm, pâ¯<â¯0.001; short-term 10.56⯱â¯0.15â¯mm vs mid-term 10.02⯱â¯0.11â¯mm, pâ¯=â¯0.021). LV mass index markedly decreased during follow-up (time, pâ¯=â¯0.001: preoperative 129.60⯱â¯3.55â¯g/m2 vs short-term 119.26⯱â¯3.19â¯g/m2, pâ¯=â¯0.009; preoperative 129.60⯱â¯3.55â¯g/m2 vs mid-term 115.79⯱â¯3.62â¯g/m2, pâ¯=â¯0.003). LV function was improved, but not significantly so, during follow-up. Strict blood pressure control had no influence on LV remodeling. True lumen followed a continuous enlargement trend in terms of proximal thoracic aorta and celiac trunk level during follow-up. CONCLUSIONS: TEVAR can reverse LV remodeling and LV hypertrophy in patients with aTBAD during follow-up.
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Aorta Torácica/cirurgia , Aneurisma da Aorta Torácica/cirurgia , Dissecção Aórtica/cirurgia , Procedimentos Endovasculares/métodos , Ventrículos do Coração/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Remodelação Ventricular/fisiologia , Dissecção Aórtica/complicações , Dissecção Aórtica/fisiopatologia , Aorta Torácica/diagnóstico por imagem , Aneurisma da Aorta Torácica/complicações , Aneurisma da Aorta Torácica/diagnóstico , Angiografia por Tomografia Computadorizada , Ecocardiografia , Feminino , Seguimentos , Ventrículos do Coração/diagnóstico por imagem , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico , Hipertrofia Ventricular Esquerda/etiologia , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
The sulfobetaine (SB) moiety, which comprises a quaternary ammonium group linked to a negatively charged sulfonate ester, is known to impart nonfouling properties to interfaces coated with polysulfobetaines or grafted with SB-polymeric brushes. Increasingly, evidence emerges that the SB group is, overall, a better antifouling group than the phosphorylcholine (PC) moiety extensively used in the past. We report here the synthesis of a series of SB-modified chitosans (CH-SB) carrying between 20 and 40 mol % SB per monosaccharide unit. Chitosan (CH) itself is a naturally derived copolymer of glucosamine and N-acetyl-glucosamine linked with a ß-1,4 bond. Analysis by quartz crystal microbalance with dissipation (QCM-D) indicates that CH-SB films (thickness â¼ 20 nm) resist adsorption of bovine serum albumin (BSA) with increasing efficiency as the SB content of the polymer augments (surface coverage â¼ 15 µg cm-2 for films of CH with 40 mol % SB). The cell adhesivity of CH-SB films coated on glass was assessed by determining the spreading dynamics of CT26 cell aggregates. When placed on chitosan films, known to be cell-adhesive, the CT26 cell aggregates spread by forming a cell monolayer around them. The spreading of CT26 cell aggregates on zwitterion-modified chitosans films is thwarted remarkably. In the cases of CH-SB30 and CH-SB40 films, only a few isolated cells escape from the aggregates. The extent of aggregate spreading, quantified based on the theory of liquid wetting, provides a simple in vitro assay of the nonfouling properties of substrates toward specific cell lines. This assay can be adopted to test and compare the fouling characteristics of substrates very different from the chemical viewpoint.
Assuntos
Betaína/análogos & derivados , Quitosana/análogos & derivados , Adsorção/efeitos dos fármacos , Animais , Betaína/síntese química , Betaína/química , Bovinos , Agregação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quitosana/síntese química , Camundongos , Soroalbumina Bovina/químicaRESUMO
This study describes chitosan-phosphorylcholine (CH-PC) films able to support the formation of cell aggregates (spheroids), which are important for tissue engineering and pharmacological studies. The surface topography, charge, thickness, and rheology of CH-PC thin films were characterized by AFM, zeta-potential measurements, SPR spectroscopy, and QCM-D measurements. The CH-PC films are highly hydrated gels, independently of the level of PC incorporation (15-40 mol-% PC/glucosamine units). QCM-D studies established that the amount of fibrinogen adsorbed on CH-PC films decreased with increasing PC content. CH-PC surfaces underwent a transition from moderately cell-adhesive (CH-PC15) to non-adhesive (CH-PC40). Optical micrographs of HUVEC and MCF-7 cell lines cultured on CH-PC surfaces showed that they form spheroids on CH-PC25 and CH-PC40 films.
Assuntos
Agregação Celular/efeitos dos fármacos , Quitosana/farmacologia , Fosforilcolina/farmacologia , Quitosana/química , Células Endoteliais da Veia Umbilical Humana , Humanos , Células MCF-7 , Fosforilcolina/química , Engenharia TecidualRESUMO
In addition to its role in the regulation of sex-related processes, 17ß-estradiol (E2) participates in the prevention and treatment of cardiovascular diseases via nongenomic pathways mediated by estrogen receptors (ER-α) located in the cell membrane. To achieve specific nongenomic activity of E2, we linked E2 (4.4 mol %) to chitosan-phosphorylcholine (CH-PC) (20 mol % PC). Injections of ER-α solutions (5 to 100 nmol L(-1)) over rehydrated CH-PC-E2 thin films led to permanent adsorption of ER-α to the film surface, as detected by quartz crystal microbalance with dissipation (QCM-D). However, ER-α did not bind onto CH-PC-E2 films formed in situ and never dried. X-ray photoelectron spectroscopy (XPS) analysis of spin-cast CH-PC-E2 films revealed significant E2 enrichment of the topmost section of the film, attributed to the preferential migration of E2 toward the film/air interface upon drying. Mechanical analysis of CH-PC-E2 films in the frequency domain probed by QCM-D indicated that rehydrated films behave as an entangled network with junction points formed by self-assembly of hydrophobic E2 moieties and by ion pairing among PC groups, whereas films formed in situ are entangled polymer solutions with temporary junctions. The structural analysis presented offers useful guidelines for the study of amphiphilic biomacromolecules designed for therapeutic use as thin films.