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1.
Theranostics ; 11(19): 9705-9720, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34646394

RESUMO

Metastasis is the major cause of high mortality in lung cancer. Exploring the underlying mechanisms of metastasis thus holds promise for identifying new therapeutic strategies that may enhance survival. Methods: We applied quantitative mass spectrometry to compare protein expression profiles between primary and metastatic lung cancer cells whilst investigating metastasis-related molecular features. Results: We discovered that BCAT1, the key enzyme in branched-chain amino acid metabolism, is overexpressed at the protein level in metastatic lung cancer cells, as well as in metastatic tissues from lung cancer patients. Analysis of transcriptomic data available in the TCGA database revealed that increased BCAT1 transcription is associated with poor overall survival of lung cancer patients. In accord with a critical role in metastasis, shRNA-mediated knockdown of BCAT1 expression reduced migration of metastatic cells in vitro and the metastasis of these cells to distal organs in nude mice. Mechanistically, high levels of BCAT1 depleted α-ketoglutarate (α-KG) and promoted expression of SOX2, a transcription factor regulating cancer cell stemness and metastasis. Conclusion: Our findings suggest that BCAT1 plays an important role in promoting lung cancer cell metastasis, and may define a novel pathway to target as an anti-metastatic therapy.

2.
Nat Commun ; 12(1): 5072, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417473

RESUMO

In vivo bioprinting has recently emerged as a direct fabrication technique to create artificial tissues and medical devices on target sites within the body, enabling advanced clinical strategies. However, existing in vivo bioprinting methods are often limited to applications near the skin or require open surgery for printing on internal organs. Here, we report a ferromagnetic soft catheter robot (FSCR) system capable of in situ computer-controlled bioprinting in a minimally invasive manner based on magnetic actuation. The FSCR is designed by dispersing ferromagnetic particles in a fiber-reinforced polymer matrix. This design results in stable ink extrusion and allows for printing various materials with different rheological properties and functionalities. A superimposed magnetic field drives the FSCR to achieve digitally controlled printing with high accuracy. We demonstrate printing multiple patterns on planar surfaces, and considering the non-planar surface of natural organs, we then develop an in situ printing strategy for curved surfaces and demonstrate minimally invasive in vivo bioprinting of hydrogels in a rat model. Our catheter robot will permit intelligent and minimally invasive bio-fabrication.


Assuntos
Bioimpressão , Cateteres , Imãs/química , Robótica , Animais , Linhagem Celular , Elasticidade , Condutividade Elétrica , Humanos , Hidrogéis/química , Fígado/diagnóstico por imagem , Ratos Sprague-Dawley , Suínos , Tomografia Computadorizada por Raios X , Viscosidade
3.
J Ethnopharmacol ; 281: 114563, 2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34438033

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The genus Amomum belonging to the family Zingiberaceae, is mainly distributed in tropical regions of Asia and Oceania. Their fruits and seeds are valuable traditional medicine and used extensively, particularly in South China, India, Malaysia, and Vietnam. The genus Amomum has long been used for treating gastric diseases, digestive disorder, cancer, hepatopathy, malaria, etc. AIMS OF THE REVIEW: The main purpose of this review is to provide the available information on the traditional medicinal uses, phytochemistry, and pharmacology aspects of the genus Amomum in order to explore the trends and perspectives for further studies on its non-volatile constituents. MATERIALS AND METHODS: The present review collected the literatures published prior to 2020 on the traditional medicinal uses, phytochemistry, and pharmacology of the genus Amomum. The available literatures were extracted from scientific databases, such as Sci-finder, PubMed, Web of Science, Google Scholar, Baidu Scholar, and CNKI, books, and others. RESULTS: Herein, we summarize all 166 naturally occurring non-volatile compounds from 16 plants of the genus Amomum reported in 171 references, including flavonoids, terpenoids, diarylheptanoids, coumarins, etc. Triterpenes and flavonoids are the main constituents among these compounds and maybe play an important role in the activities directly or indirectly. As traditional medicine, the plants from the genus Amomum have been usually used in some traditional herbal prescriptions, and pharmacological researches in vitro and in vivo revealed that the extracts possessed significant antioxidant, anti-inflammatory, anti-allergic activities, etc. CONCLUSION: The review systematically summarizes current studies on traditional medicinal uses, phytochemistry, pharmacological activity on the plants from the genus Amomum. To date, the majority of publications still focused on the research of volatile constituents. However, the promising preliminary data of non-volatile constituents indicated the research potential of this genus in phytochemical and pharmacological aspects. Furthermore, the further in-depth investigations on the safety, efficacy, as well as the stereo-chemistry and structure-activity relationships of pure compounds from this genus are essential in the future.

4.
Eur J Med Chem ; 224: 113696, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34274828

RESUMO

The antimicrobial resistance (AMR) is an intractable problem for the world. Metal ions are essential for the cell process and biological function in microorganisms. Many metal-based complexes with the potential for releasing ions are more likely to be absorbed for their higher lipid solubility. Hence, this review highlights the clinical potential of organometallic compounds for the treatment of infections caused by bacteria or fungi in recent five years. The common scaffolds, including antimicrobial peptides, N-heterocyclic carbenes, Schiff bases, photosensitive-grand-cycle skeleton structures, aliphatic amines-based ligands, and special metal-based complexes are summarized here. We also discuss their therapeutic targets and the risks that should be paid attention to in the future studies, aiming to provide information for researchers on metal-based complexes as antimicrobial agents and inspire the design and synthesis of new antimicrobial drugs.

5.
J Control Release ; 337: 224-235, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34298057

RESUMO

Aortic dissection (AD) is a life-threatening disease featured by the dissection of intimal layer and the formation of a blood-filled false lumen within the aortic wall. Recent studies revealed that the formation and progression of AD lesions is closely related to vascular inflammation and macrophage infiltration. However, the potential efficacy of anti-inflammatory therapy on the prevention and treatment of AD has not been extensively investigated. Herein, we proposed a biomimetic anti-inflammatory liposome (PM/TN-CCLP) co-loaded with curcumin and celecoxib (CC), modified with cell-penetrating TAT-NBD fusion peptide (TN), and further camouflaged by isolated macrophage plasma membrane (PM), as a potential nanotherapy for AD. In vitro results showed that PM/TN-CCLP exhibited low cytotoxicity and elevated cellular uptake by inflammatory macrophages, and prominently inhibited the transendothelial migration, inflammatory responses and ROS generation of macrophages. Moreover, the PM/TN-CCLP treatment significantly prevented the H2O2-induced smooth muscle cell apoptosis. In vivo experiments were performed on the acute and chronic AD mouse models, respectively. The results verified the elevated accumulation of PM-camouflaged liposome at the aorta lesions. Further, the anti-inflammatory liposomes, especially PM/TN-CCLP, could reduce the rupture rate of dissection, prevent the loss of elastic fibers, and reduce MMP-9 expression as well as macrophage infiltration in the aortic lesions. Notably, as compared with free drugs and TN-CCLP, the PM/TN-CCLP treatment displayed the longest survival period along with the minimal aortic injury on both acute and chronic AD mice. Taken together, the present study suggested that the macrophage-biomimetic anti-inflammatory nanotherapy would be a promising strategy for the prevention and therapy of aortic dissection.

6.
Bioorg Med Chem ; 36: 116095, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33735687

RESUMO

Isocitrate dehydrogenase (IDH) is one key rate-limiting enzyme in the tricarboxylic acid cycle, which is related to various cancers. Tomatillo (Physalis ixocarpa), a special tomato, is widely consumed as nutritious vegetable in Mexico, USA, etc. As a rich source for withanolides, the fruits of P. ixocarpa were investigated, leading to the isolation of 11 type-A withanolides including 4 new ones (1 is an artificial withanolide). All these withanolides were evaluated for their inhibition on mutant IDH1 enzyme activity. Among them, physalin F (11) exhibited potent enzyme inhibitory activity and binding affinity with mutant IDH1. It inhibits the proliferation of HT1080 cells by selectively inhibiting the activity of mutant IDH1. Since Ixocarpalactone A, another major type-B withanolide in this plant, could act on another energy metabolism target PHGDH, the presence of different types of withanolides in tomatillo and their synergistic effect could make it a potential antitumor functional food or drug.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Inibidores Enzimáticos/farmacologia , Isocitrato Desidrogenase/antagonistas & inibidores , Physalis/química , Extratos Vegetais/farmacologia , Vitanolídeos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Humanos , Isocitrato Desidrogenase/genética , Estrutura Molecular , Mutação , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Vitanolídeos/química , Vitanolídeos/isolamento & purificação
7.
Cell Oncol (Dordr) ; 44(3): 541-556, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33735398

RESUMO

BACKGROUND: Metabolic changes have been recognized as an important hallmark of cancer cells. Cancer cells can promote their own growth and proliferation through metabolic reprogramming. Particularly, serine metabolism has frequently been reported to be dysregulated in tumor cells. 3-Phosphoglycerate dehydrogenase (PHGDH) catalyzes the first step in the serine biosynthesis pathway and acts as a rate-limiting enzyme involved in metabolic reprogramming. PHGDH upregulation has been observed in many tumor types, and inhibition of PHGDH expression has been reported to inhibit the proliferation of PHGDH-overexpressing tumor cells, indicating that it may be utilized as a target for cancer treatment. Recently identified inhibitors targeting PHGDH have already shown effectiveness. A further in-depth analysis and concomitant development of PHGDH inhibitors will be of great value for the treatment of cancer. CONCLUSIONS: In this review we describe in detail the role of PHGDH in various cancers and inhibitors that have recently been identified to highlight progression in cancer treatment. We also discuss the development of new drugs and treatment modalities based on PHGDH targets. Overexpression of PHGDH has been observed in melanoma, breast cancer, nasopharyngeal carcinoma, parathyroid adenoma, glioma, cervical cancer and others. PHGDH may serve as a molecular biomarker for the diagnosis, prognosis and treatment of these cancers. The design and development of novel PHGDH inhibitors may have broad implications for cancer treatment. Therapeutic strategies of PHGDH inhibitors in combination with traditional chemotherapeutic drugs may provide new perspectives for precision medicine and effective personalized treatment for cancer patients.

8.
Eur J Med Chem ; 214: 113264, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33582386

RESUMO

With the change of lifestyle and the acceleration of aging process, inflammatory diseases have increasingly become one of the most vital threats to global human health. SHP2 protein is a non-receptor tyrosine phosphatase encoded by PTPN11 gene, and it is widely expressed in various tissues and cells. Numerous studies have shown that SHP2 plays important roles in the regulation of inflammatory diseases, including cancer-related inflammation, neurodegenerative diseases and metabolic diseases. In this paper, the roles of SHP2 in inflammatory diseases of various physiological systems were reviewed. At the same time, the latest SHP2 inhibitors were summarized, which will hold a promise for the therapeutic potential in future.


Assuntos
Produtos Biológicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Inflamação/tratamento farmacológico , Doenças Metabólicas/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Produtos Biológicos/química , Inibidores Enzimáticos/química , Humanos , Inflamação/metabolismo , Doenças Metabólicas/metabolismo , Estrutura Molecular , Doenças Neurodegenerativas/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo
9.
Pharmacol Res ; 164: 105367, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33307221

RESUMO

Accelerated glucose metabolism is a common feature of cancer cells. Hexokinase 2 (HK2) as the rate-limiting enzyme catalyzes the first step of glucose metabolism. It is overexpressed in most of the human cancers and has been a promising target for cancer therapy. Here, we report a novel selective HK2 inhibitor Benitrobenrazide (BNBZ), with nanomolar inhibitory potency. In vitro, BNBZ directly binds to HK2, induces apoptosis, and inhibits proliferation of HK2-overexpressed cancer cells. BNBZ also significantly inhibits the glycolysis of SW1990 cells by targeting HK2. The knockdown or knockout of HK2 expression in SW1990 cells can reduce their sensitivity to BNBZ. Additionally, oral administration of BNBZ can effectively inhibit tumor growth in SW1990 and SW480 xenograft models. In general, BNBZ significantly inhibited glycolysis and cancer cell proliferation in vitro and in vivo by directly targeting HK2 with high potency and low toxicity, and can be developed as a novel HK2 small-molecule candidate drug for future cancer therapeutics.

10.
iScience ; 23(10): 101642, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33043282

RESUMO

COVID-19 broke out in the end of December 2019 and is still spreading rapidly, which has been listed as an international concerning public health emergency. We found that the Spike protein of SARS-CoV-2 contains a furin cleavage site, which did not exist in any other betacoronavirus subtype B. Based on a series of analysis, we speculate that the presence of a redundant furin cut site in its Spike protein is responsible for SARS-CoV-2's stronger infectious nature than other coronaviruses, which leads to higher membrane fusion efficiency. Subsequently, a library of 4,000 compounds including approved drugs and natural products was screened against furin through structure-based virtual screening and then assayed for their inhibitory effects on furin activity. Among them, an anti-parasitic drug, diminazene, showed the highest inhibition effects on furin with an IC50 of 5.42 ± 0.11 µM, which might be used for the treatment of COVID-19.

11.
Adv Healthc Mater ; 9(20): e2001116, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32940970

RESUMO

Thromboembolic and infectious complications stemming from the use of cardiovascular medical devices are still common and result in significant morbidity and mortality. There is no strategy to date that effectively addresses both challenges at the same time. Various surface modification strategies (e.g., silver, heparin, and liquid-impregnated surfaces) are proposed yet each has several limitations and shortcomings. Here, it is shown that the incorporation of an ultrathin and mechanically robust hydrogel layer reduces bacterial adhesion to medical-grade tubing by 95%. It is additionally demonstrated, through a combination of in vitro and in vivo tests, that the hydrogel layer significantly reduces the formation and adhesion of blood clots to the tubing without affecting the blood's intrinsic clotting ability. The adhesion of clots to the tubing walls is reduced by over 90% (in vitro model), which results in an ≈60% increase in the device occlusion time (time before closure due to clot formation) in an in vivo porcine model. The advantageous properties of this passive coating make it a promising surface material candidate for medical devices interfacing with blood.


Assuntos
Aderência Bacteriana , Hidrogéis , Animais , Prata , Suínos
12.
Drug Dev Ind Pharm ; 46(11): 1809-1818, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32903067

RESUMO

Arsenic trioxide (ATO) is first-line drug for acute promyelocytic leukemia. Clinically, the continuously slow intravenous infusion is adopted to maintain effective blood concentration and reduce toxic effects, but it causes poor patient' compliance for a considerable infusion period. To overcome these disadvantages, we developed an oral ATO sustained-release preparation which was constructed via the ATO core pellets prepared by extrusion spheronization and followed by a coating membrane by fluid-bed technology. The prepared coated pellets displayed a round surface and uniform particle size. All in vitro release profiles of ATO pellets in different pH media and rotation speeds had no statistical difference. Importantly, the coated pellets can release completely in 12 h without obvious burst release. There was no distinct change in appearance and release behaviors in stability experiments. In vivo pharmacokinetics was studied by one-time intragastric administration of rats. Compared with free drug, the AUC0-∞ of the ATO coated pellets was 2.3-fold higher, indicating the oral bioavailability was significantly increased. Cmax decreased by about a half and Tmax extended about 15 h. In particularly, the ATO level at 96 h only decreased about 20% of Cmax , suggesting that the ATO sustained-release preparation could not only decrease the peak concentration, but also maintain a relatively constant blood concentration for a long period. Further, the in vivo absorption could be well predicted by in vitro release experiments. Therefore, the ATO sustained-release preparation formulated by the mature preparation technology, possessing satisfactory stability and improving bioavailability, had great application potentials for industrialization.


Assuntos
Trióxido de Arsênio , Implantes de Medicamento , Animais , Disponibilidade Biológica , Preparações de Ação Retardada , Ratos , Solubilidade
13.
AAPS PharmSciTech ; 21(7): 259, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32914285

RESUMO

Nanomedicines such as liposomes have been widely exploited in the treatment of tumors, and are also involved in combination therapies to enhance anti-tumor efficacy and reduce side effects. However, few studies have systematically discussed the significance and optimized regimens for nanomedicine-based combination therapy. In this study, we used anti-inflammatory and anti-tumor liposomes for co-administration, and compared three regimens: intermittent, metronomic, or sequential administration (IA, MA, and SA). The anti-inflammatory liposome HA/TN-CCLP was constructed in our previous research, which co-loaded curcumin (CUR) and celecoxib (CXB), modified with TAT-NBD peptide (TN) and finally coated with hyaluronic acid (HA), thereby inhibiting NF-κB and STAT3 pathways in the treatment of metastatic breast cancer. Furthermore, doxorubicin liposomes with and without TN modification (namely TN-DOXLP and DOXLP) were constructed and administrated with HA/TN-CCLP. The anti-tumor and anti-metastasis efficacy of different regimens was investigated. Results showed that in vitro cytotoxicity of DOXLP and TN-DOXLP was significantly enhanced when combined with HA/TN-CCLP. In vivo experiments also revealed the superiority of three combination therapies in inhibiting tumor growth, prolonging the survival of tumor-bearing mice, inducing apoptosis, and reducing lung metastases. In particular, the combination therapy could reduce MDSCs (Gr-1+/CD11b+) and CSCs (CD44+/CD24+) infiltration, which are two important factors in tumor metastasis and recurrence. Among three regimens, sequential administration (SA) showed the best therapeutic outcome and was especially effective for the inhibition of CSCs. In general, the results demonstrated that combination therapy, particularly the sequential administration of anti-inflammatory and anti-tumor liposome, was superior to monotherapy in inhibiting the development and metastasis of inflammation-related tumors.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Lipossomos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Celecoxib/farmacologia , Curcumina/farmacologia , Doxorrubicina/análogos & derivados , Feminino , Humanos , Receptores de Hialuronatos , Ácido Hialurônico/farmacologia , Camundongos , Nanomedicina , Metástase Neoplásica , Polietilenoglicóis
14.
Eur J Med Chem ; 207: 112698, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32858471

RESUMO

Transcription is the fundamental process in all living organisms. A variety of important proteins, such as NRs, BETs, HDACs and many others are involved in transcription process. In general, overexpression of these proteins would cause many diseases. Some approved therapeutics employed inhibitors to regulate the transcription process, however, the results are far from satisfying. Therefore, it is in high demand to develop new technology to improve the therapeutic effects. In recent years, proteolysis-targeting chimaera (PROTAC) turned out to be a novel efficient therapeutic method to treat various diseases which were caused by proteins overexpression. PROTAC molecules are bifunctional small molecules that simultaneously bind a target protein and an E3-ubiquitin ligase, thus causing ubiquitination and subsequent degradation of the target protein by the proteasome. In contrast to traditional inhibitors, PROTACs showed higher efficiency to tackle the diseases which were caused by protein overexpression due to their excellent performance for degrading target proteins in transcription regulation. In this review, 29 kinds of PROTACs targeting transcription regulator proteins are summarized, and meanwhile the advantages of PROTACs are highlighted. Furthermore, several examples of PROTACs regulating the transcription for the treatment of diseases and functioning as tools for biological research are also disscussed.


Assuntos
Descoberta de Drogas/métodos , Proteólise/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Ativação Transcricional/efeitos dos fármacos , Animais , Histona Desacetilases/metabolismo , Humanos , Complexo de Endopeptidases do Proteassoma/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/efeitos dos fármacos
15.
J Med Chem ; 63(15): 8146-8156, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32667202

RESUMO

Tumor necrosis factor α (TNF-α) is an important therapeutic target for rheumatoid arthritis, inflammatory bowel disease, and septic hepatitis. In this study, structure-based virtual ligand screening combined with in vitro and in vivo assays were applied. A lead compound, benpyrine, could directly bind to TNF-α and block TNF-α-trigged signaling activation. Furthermore, the endotoxemic murine model showed that benpyrine could attenuate TNF-α-induced inflammation, thereby reducing liver and lung injury. Meanwhile, administration of benpyrine by gavage significantly relieved the symptoms of collagen-induced arthritis and imiquimod-induced psoriasiform inflammation in mice. Thus, our study discovered a novel, highly specific, and orally active small-molecule TNF-α inhibitor that is potentially useful for treating TNF-α-mediated inflammatory and autoimmune disease.


Assuntos
Cromanos/administração & dosagem , Cromanos/química , Descoberta de Drogas/métodos , Indóis/administração & dosagem , Indóis/química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Administração Oral , Animais , Camundongos , Camundongos Endogâmicos BALB C , Células RAW 264.7 , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismo
16.
Acta Pharm Sin B ; 10(5): 766-788, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32292689

RESUMO

SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths. There are currently no registered therapies for treating coronavirus infections. Because of time consuming process of new drug development, drug repositioning may be the only solution to the epidemic of sudden infectious diseases. We systematically analyzed all the proteins encoded by SARS-CoV-2 genes, compared them with proteins from other coronaviruses, predicted their structures, and built 19 structures that could be done by homology modeling. By performing target-based virtual ligand screening, a total of 21 targets (including two human targets) were screened against compound libraries including ZINC drug database and our own database of natural products. Structure and screening results of important targets such as 3-chymotrypsin-like protease (3CLpro), Spike, RNA-dependent RNA polymerase (RdRp), and papain like protease (PLpro) were discussed in detail. In addition, a database of 78 commonly used anti-viral drugs including those currently on the market and undergoing clinical trials for SARS-CoV-2 was constructed. Possible targets of these compounds and potential drugs acting on a certain target were predicted. This study will provide new lead compounds and targets for further in vitro and in vivo studies of SARS-CoV-2, new insights for those drugs currently ongoing clinical studies, and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections.

17.
J Am Soc Mass Spectrom ; 31(7): 1380-1388, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32268065

RESUMO

We developed a normalization method utilizing the expression levels of a panel of endogenous proteins as normalization standards (EPNS herein). We tested the validity of the method using two sets of tandem mass tag (TMT)-labeled data and found that this normalization method effectively reduced global intensity bias at the protein level. The coefficient of variation (CV) of the overall median was reduced by 55% and 82% on average, compared to the reduction by 72% and 86% after normalization using the upper quartile. Furthermore, we used differential protein expression analysis and statistical learning to identify biomarkers for colorectal cancer from a CPTAC data set. The expression changes of a panel of proteins, including NUP205, GTPBP4, CNN2, GNL3, and S100A11, all of which highly correlate with colorectal cancer. Applying these five proteins as model features, random forest modeling obtained prediction results with the maximum AUC of 0.9998 using EPNS-normalized data, comparing favorably to the AUC of 0.9739 using the raw data. Thus, the normalization method based on EPNS reduced the global intensity bias and is applicable for quantitative proteomic analysis.


Assuntos
Modelos Estatísticos , Proteoma/análise , Proteômica/métodos , Proteômica/normas , Área Sob a Curva , Biomarcadores Tumorais/análise , Neoplasias Colorretais/metabolismo , Humanos
18.
Nat Commun ; 11(1): 1071, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-32103027

RESUMO

The adhesion of soft connective tissues (tendons, ligaments, and cartilages) on bones in many animals can maintain high toughness (∽800 J m-2) over millions of cycles of mechanical loads. Such fatigue-resistant adhesion has not been achieved between synthetic hydrogels and engineering materials, but is highly desirable for diverse applications such as artificial cartilages and tendons, robust antifouling coatings, and hydrogel robots. Inspired by the nanostructured interfaces between tendons/ligaments/cartilages and bones, we report that bonding ordered nanocrystalline domains of synthetic hydrogels on engineering materials can give a fatigue-resistant adhesion with an interfacial fatigue threshold of 800 J m-2, because the fatigue-crack propagation at the interface requires a higher energy to fracture the ordered nanostructures than amorphous polymer chains. Our method enables fatigue-resistant hydrogel coatings on diverse engineering materials with complex geometries. We further demonstrate that the fatigue-resistant hydrogel coatings exhibit low friction and low wear against natural cartilages.


Assuntos
Cartilagem/fisiologia , Hidrogéis/química , Teste de Materiais , Tíbia/fisiologia , Engenharia Tecidual/métodos , Animais , Adesão Celular/fisiologia , Galinhas , Modelos Moleculares , Propriedades de Superfície
19.
Chem Biodivers ; 17(2): e1900531, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31825561

RESUMO

Euphorbia factor L3 , a lathyrane diterpenoid extracted from Euphorbia lathyris, was found to display good anti-inflammatory activity with very low cytotoxicity. To find more potent anti-inflammatory drugs, two series of Euphorbia factor L3 derivatives with fatty and aromatic acids were designed and synthesized. Among them, lathyrane derivative 5n exhibited most potent inhibition on LPS-induced NO production in RAW264.7 cells with no obvious cytotoxicity. To determine the key characteristics of Euphorbia factor L3 derivatives that contribute to anti-inflammatory activity, we conducted a structure-activity relationship study of these compounds.


Assuntos
Anti-Inflamatórios/síntese química , Diterpenos/química , Euphorbia/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/síntese química , Diterpenos/farmacologia , Euphorbia/metabolismo , Lipopolissacarídeos/toxicidade , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Células RAW 264.7 , Relação Estrutura-Atividade
20.
Front Pharmacol ; 10: 1446, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31849686

RESUMO

Traditional Chinese medicines (TCMs) represent one form of complementary and alternative medicine. The popularity and complexity in production make them attractive and vulnerable to adulteration in stages ranging from planting to production. Adulteration refers to the addition of extraneous, improper, or inferior ingredients that should not be present in TCMs. To detect and combat adulterated TCMs, supplementary testing methods (STMs), which expand the capability of routine testing standards, have been applied in China since 2003. From 2003 to 2017, a total of 184 STMs for TCMs were approved by the Chinese national drug regulatory authority. By assessing these STMs, this research intends to identify those TCMs vulnerable to adulteration, to list common adulterants, and to characterize the techniques of analysis. The results show that adulteration of TCMs can be classified into three main categories: the addition of undeclared drugs/chemical substances, substitution with non-drug components, and the addition of foreign non-drug materials. The top five therapeutic areas of TCMs vulnerable to adulteration are diabetes, calm and sleep, sexual dysfunction, pain relief, and rheumatism. A total of 166 adulterants were detected in the adulterated TCM preparations and herbal products studied here, with 158 adulterants in TCM preparations and 43 in herbal products, with 35 adulterants in common. Each STM consists of different pharmaceutical analysis techniques, including tests for physical-chemical properties, chromatography, spectroscopic techniques, and mass spectrometry. The analytical methodology of STMs relies on the combination of these techniques, with HPLC ranking the highest percentage (76.1%) and physical-chemical techniques the lowest percentage (11.4%). This research shows that STMs have played a crucial role in combating adulterated TCMs. However, STMs represent merely a product testing-centered regulatory strategy. The inspection of cultivation and manufacturing processes should also be strengthened. More importantly, the awareness and self-discipline of TCM manufacturers in implementing good manufacturing practices and regulating the planting and cultivation of raw materials should be improved.

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