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1.
J Med Virol ; 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34506640

RESUMO

SARS-CoV-2 is a newly discovered beta coronavirus at the end of 2019, which is highly pathogenic and poses a serious threat to human health. In this paper, 1875 SARS-CoV-2 whole genome sequences and the sequence coding spike protein (S gene) sampled from the United States were used for bioinformatics analysis to study the molecular evolutionary characteristics of its genome and spike protein. The MCMC method was used to calculate the evolution rate of the whole genome sequence and the nucleotide mutation rate of the S gene. The results showed that the nucleotide mutation rate of the whole genome was 6.677 × 10-4 substitution per site per year, and the nucleotide mutation rate of the S gene was 8.066 × 10-4 substitution per site per year, which was at a medium level compared with other RNA viruses. Our findings confirmed the scientific hypothesis that the rate of evolution of the virus gradually decreases over time. We also found 13 statistically significant positive selection sites in the SARS-CoV-2 genome. In addition, the results showed that there were 101 nonsynonymous mutation sites in the amino acid sequence of S protein, including seven putative harmful mutation sites. This paper has preliminarily clarified the evolutionary characteristics of SARS-CoV-2 in the United States, providing a scientific basis for future surveillance and prevention of virus variants.

2.
ACS Appl Mater Interfaces ; 13(33): 38979-38989, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433249

RESUMO

Chronic infections caused by Pseudomonas aeruginosa pose severe threats to human health. Traditional antibiotic therapy has lost its total supremacy in this battle. Here, nanoplatforms activated by the clinical microenvironment are developed to treat P. aeruginosa infection on the basis of dynamic borate ester bonds. In this design, the nanoplatforms expose targeted groups for bacterial capture after activation by an acidic infection microenvironment, resulting in directional transport delivery of the payload to bacteria. Subsequently, the production of hyperpyrexia and reactive oxygen species enhances antibacterial efficacy without systemic toxicity. Such a formulation with a diameter less than 200 nm can eliminate biofilm up to 75%, downregulate the level of cytokines, and finally promote lung repair. Collectively, the biomimetic design with phototherapy killing capability has the potential to be an alternative strategy against chronic infections caused by P. aeruginosa.


Assuntos
Antibacterianos/química , Verde de Indocianina/química , Nanocápsulas/química , Fármacos Fotossensibilizantes/química , Polímeros/química , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/radioterapia , Células A549 , Animais , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Composição de Medicamentos , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Humanos , Verde de Indocianina/farmacologia , Raios Infravermelhos , Masculino , Metacrilatos/química , Camundongos Endogâmicos BALB C , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Polietilenoglicóis/química , Pseudomonas aeruginosa/efeitos dos fármacos
3.
Molecules ; 26(14)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34299538

RESUMO

Trichophyton rubrum causes ringworm worldwide. Citral (CIT), extracted from Pectis plants, is a monoterpene and naturally composed of geometric isomers neral (cis-citral) and geranial (trans-citral). CIT has promising antifungal activities and ergosterol biosynthesis inhibition effects against several pathogenic fungi. However, no study has focused on neral and geranial against T. rubrum, which hinders the clinical application of CIT. This study aimed to compare antifungal activities of neral and geranial and preliminarily elucidate their ergosterol biosynthesis inhibition mechanism against T. rubrum. Herein, the disc diffusion assays, cellular leakage measurement, flow cytometry, SEM/TEM observation, sterol quantification, and sterol pattern change analyses were employed. The results showed geranial exhibited larger inhibition zones (p < 0.01 or 0.05), higher cellular leakage rates (p < 0.01), increased conidia with damaged membranes (p < 0.01) within 24 h, more distinct shriveled mycelium in SEM, prominent cellular material leakage, membrane damage, and morphological changes in TEM. Furthermore, geranial possessed more promising ergosterol biosynthesis inhibition effects than neral, and both induced the synthesis of 7-Dehydrodesmosterol and Cholesta-5,7,22,24-tetraen-3ß-ol, which represented marker sterols when ERG6 was affected. These results suggest geranial is more potent than neral against T. rubrum, and both inhibit ergosterol biosynthesis by affecting ERG6.


Assuntos
Monoterpenos Acíclicos/farmacologia , Antifúngicos/farmacologia , Arthrodermataceae/efeitos dos fármacos , Dermatomicoses/tratamento farmacológico , Ergosterol/farmacologia , Testes de Sensibilidade Microbiana/métodos , Monoterpenos/farmacologia , Micélio/efeitos dos fármacos , Extratos Vegetais/farmacologia , Esporos Fúngicos/efeitos dos fármacos
4.
Artigo em Inglês | MEDLINE | ID: mdl-34081589

RESUMO

To alleviate the sparsity issue, many recommender systems have been proposed to consider the review text as the auxiliary information to improve the recommendation quality. Despite success, they only use the ratings as the ground truth for error backpropagation. However, the rating information can only indicate the users' overall preference for the items, while the review text contains rich information about the users' preferences and the attributes of the items. In real life, reviews with the same rating may have completely opposite semantic information. If only the ratings are used for error backpropagation, the latent factors of these reviews will tend to be consistent, resulting in the loss of a large amount of review information. In this article, we propose a novel deep model termed deep rating and review neural network (DRRNN) for recommendation. Specifically, compared with the existing models that adopt the review text as the auxiliary information, DRRNN additionally considers both the target rating and target review of the given user-item pair as ground truth for error backpropagation in the training stage. Therefore, we can keep more semantic information of the reviews while making rating predictions. Extensive experiments on four publicly available datasets demonstrate the effectiveness of the proposed DRRNN model in terms of rating prediction.

5.
Artigo em Inglês | MEDLINE | ID: mdl-34097606

RESUMO

Designing effective architectures is one of the key factors behind the success of deep neural networks. Existing deep architectures are either manually designed or automatically searched by some Neural Architecture Search (NAS) methods. However, even a well-designed/searched architecture may still contain many nonsignificant or redundant modules/operations (e.g., some intermediate convolution or pooling layers). Thus, it is necessary to optimize the operations inside an architecture to improve the performance without introducing extra computational cost. To this end, we have proposed a Neural Architecture Transformer (NAT) method which casts the optimization problem into a Markov Decision Process (MDP) and seeks to replace the redundant operations with more efficient operations, such as skip or null connection. Based on NAT, we propose a Neural Architecture Transformer++ (NAT++) method which further enlarges the set of candidate transitions to improve the performance of architecture optimization. Specifically, we present a two-level transition rule to obtain valid transitions, i.e., allowing operations to have more efficient types (e.g., convolution->separable convolution) or smaller kernel sizes (e.g., 5x5->3x3). We further propose a Binary-Masked Softmax (BMSoftmax) layer to omit the possible invalid transitions. Extensive experiments on several benchmark datasets demonstrate the effectiveness of the proposed methods.

6.
Oncologist ; 26(8): 649-e1313, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33749934

RESUMO

LESSONS LEARNED: MET overexpression is uncommon, and positive MET immunohistochemistry (1+/2+) was an independent positive prognostic factor for response rate and progression-free survival. Whether MET overexpression can be considered a potential predictive biomarker and be used as an inclusion criterion is worth investigating in a future study. BACKGROUND: Metatinib tromethamine tablet (metatinib) is a small molecule receptor kinase inhibitor targeting both c-MET and vascular endothelial growth factor receptor 2. This phase I trial aimed to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD), pharmacokinetics, safety, and efficacy of metatinib in patients with advanced solid tumors. METHODS: Eligible patients received a single dose of metatinib in a 3 + 3 dose-escalation design with dose levels of 25-800 mg/day, after a single dose on day 1, then 2 days off, and then a multidose schedule of once-daily doses for 25 consecutive days (days 4-28). Primary endpoints were MTD and safety; secondary and exploratory endpoints included pharmacokinetics (PK), efficacy, and biomarkers. RESULTS: Eighteen patients (including nine patients with hepatocellular carcinoma [HCC]) received at least one dose of study drug (one patient quit the study without continuous multiple-dose administration after receiving a single dose of metatinib). Hand-foot skin reaction, diarrhea, and liver dysfunction were the DLTs, and 200 mg/day was the MTD. The most common treatment-related adverse events (TRAEs) were skin toxicity (50%), diarrhea (33.3%), and liver dysfunction (27.8%). Three patients (only one of six in the 200 mg/day cohort; the other two in the 300 mg/day cohort) experienced severe TRAEs: one patient with severe liver dysfunction and two patients with severe liver dysfunction and skin toxicity, respectively. Pharmacokinetics assessment indicated that metatinib was rapidly absorbed and metabolized to the formation of reactive metabolite, SCR-1510, after single-dose administration. The mean time taken to achieve maximum concentration and terminal elimination half-life of SCR-1510 was approximately 2.0-3.0 hours and ranged from 8 to 14 hours. Two patients had partial responses. The objective response rate and disease control rate (DCR) were 11.1% and 61.1%, respectively. The median progression-free survival (PFS) was 2.75 months. CONCLUSION: Metatinib administration of 200 mg/day was well tolerated, safe, and effective. The MTD was 200 mg/day, which should be recommended in further investigations.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Comprimidos , Trometamina , Fator A de Crescimento do Endotélio Vascular
7.
World J Gastroenterol ; 27(9): 835-853, 2021 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-33727773

RESUMO

BACKGROUND: Liver injury is common and also can be fatal, particularly in severe or critical patients with coronavirus disease 2019 (COVID-19). AIM: To conduct an in-depth investigation into the risk factors for liver injury and into the effective measures to prevent subsequent mortality risk. METHODS: A retrospective cohort study was performed on 440 consecutive patients with relatively severe COVID-19 between January 28 and March 9, 2020 at Tongji Hospital, Wuhan, China. Data on clinical features, laboratory parameters, medications, and prognosis were collected. RESULTS: COVID-19-associated liver injury more frequently occurred in patients aged ≥ 65 years, female patients, or those with other comorbidities, decreased lymphocyte count, or elevated D-dimer or serum ferritin (P < 0.05). The disease severity of COVID-19 was an independent risk factor for liver injury (severe patients: Odds ratio [OR] = 2.86, 95% confidence interval [CI]: 1.78-4.59; critical patients: OR = 13.44, 95%CI: 7.21-25.97). The elevated levels of on-admission aspartate aminotransferase and total bilirubin indicated an increased mortality risk (P < 0.001). Using intravenous nutrition or antibiotics increased the risk of COVID-19-associated liver injury. Hepatoprotective drugs tended to be of assistance to treat the liver injury and improve the prognosis of patients with COVID-19-associated liver injury. CONCLUSION: More intensive monitoring of aspartate aminotransferase or total bilirubin is recommended for COVID-19 patients, especially patients aged ≥ 65 years, female patients, or those with other comorbidities. Drug hepatotoxicity of antibiotics and intravenous nutrition should be alert for COVID-19 patients.


Assuntos
COVID-19/complicações , Hepatopatias/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/mortalidade , COVID-19/fisiopatologia , China/epidemiologia , Feminino , Seguimentos , Humanos , Hepatopatias/diagnóstico , Hepatopatias/mortalidade , Hepatopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida
8.
Blood Purif ; 50(6): 906-913, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33556944

RESUMO

BACKGROUND: Arteriovenous fistula (AVF) is the most common vascular access for patients undergoing hemodialysis (HD). Neointimal hyperplasia (NIH) might be a potential mechanism of AVF dysfunction. Retinol-binding protein 4 (RBP4) may play an important role in the pathogenesis of NIH. The aim of this study was to investigate whether AVF dysfunction is associated with serum concentrations of RBP4 in HD subjects. METHODS: A cohort of 65 Chinese patients undergoing maintenance HD was recruited between November 2017 and June 2019. The serum concentrations of RBP4 of each patient were measured with the ELISA method. Multivariate logistic regression was used to analyze data on demographics, biochemical parameters, and serum RBP4 level to predict AVF dysfunction events. The cutoff for serum RBP4 level was derived from the highest score obtained on the Youden index. Survival data were analyzed with the Cox proportional hazards regression analysis and Kaplan-Meier method. RESULTS: Higher serum RBP4 level was observed in patients with AVF dysfunction compared to those without AVF dysfunction events (174.3 vs. 168.4 mg/L, p = 0.001). The prevalence of AVF dysfunction events was greatly higher among the high RBP4 group (37.5 vs. 4.88%, p = 0.001). In univariate analysis, serum RBP4 level was statistically significantly associated with the risk of AVF dysfunction (OR = 1.015, 95% CI 1.002-1.030, p = 0.030). In multivariate analysis, each 1.0 mg/L increase in RBP4 level was associated with a 1.023-fold-increased risk of AVF dysfunction (95% CI for OR: 1.002-1.045; p = 0.032). The Kaplan-Meier survival analysis indicated that the incidence of AVF dysfunction events in the high RBP4 group was significantly higher than that in the low-RBP4 group (p = 0.0007). Multivariate Cox regressions demonstrated that RBP4 was an independent risk factor for AVF dysfunction events in HD patients (HR = 1.015, 95% CI 1.001-1.028, p = 0.033). CONCLUSIONS: HD patients with higher serum RBP4 concentrations had a relevant higher incidence of arteriovenous dysfunction events. Serum RBP4 level was an independent risk factor for AVF dysfunction events in HD patients.

9.
J Am Chem Soc ; 143(9): 3595-3603, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33630572

RESUMO

For nearly 30 years, considerable research effort has been focused on the development of methods for catalytic (3 + 2) cycloaddition reactions of palladium-oxyallyl species with alkenes. However, because C-O bond formation is kinetically favored, the (3 + 2) cycloadditions achieved to date have involved C-O reductive elimination. We herein report a method of lithium triflate-promoted (3 + 2) cycloaddition reactions of palladium-oxyallyl species with 1,3-dienes that proceed via a pathway terminated with C-C bond formation to give a five-membered carbocycle. Coordination of the lithium ion with the alkoxide moiety disrupts the C-O reductive elimination and forms a metal-enolate tethered π-allyl-Pd. The π-allyl-Pd moiety then accepts intramolecular allylic attack from the enolate moiety to form carbocyclic products. Furthermore, by tuning the steric properties of the palladium ligand, we could also accomplish the competing (4 + 3) cycloadditions, and thus this method provides regiodivergent access to both cyclopentanones and cycloheptanones. The reaction mechanism was investigated by DFT calculation and the origins of the regioselectivities of the cycloaddition were rationalized.

10.
J Cell Mol Med ; 25(4): 2069-2081, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33434305

RESUMO

Osteoporosis is a metabolic disease that results from oxidative stress or inflammation in renal disorders. microRNAs (miRNAs) are recently implicated to participate in osteoporosis, but the mechanism remains largely unexplored. Herein, we aimed to explore the potential role of miR-15b in osteoblast differentiation and autophagy in osteoporosis. We established osteoporosis models through ovariectomy and determined that miR-15b was highly expressed whereas USP7 and KDM6B were poorly expressed in tissue of osteoporosis mice. Treatment of silenced miR-15b resulted in the elevation of decreased bone mineral density (BMD), the maximum elastic stress and the maximum load of osteoporosis mice. In osteoblasts, miR-15 overexpression decreased proliferation but suppressed the cell differentiation and autophagy, accompanied with decreased expression of USP7. Mechanistically, miR-15 bound and inhibited USP7 expression, while overexpression of USP7 promoted autophagy of osteoblasts. USP7, importantly, strengthened the stability of KDM6B and promoted KDM6B expression. MG132 protease inhibitor increased KDM6B and USP7 expression in osteoblasts. Silencing of KDM6B reversed the promoting effect on autophagy and proliferation induced by overexpression of USP7. Taken altogether, miR-15b inhibits osteoblast differentiation and autophagy to aggravate osteoporosis by targeting USP7 to regulate KDM6B expression.


Assuntos
Autofagia/genética , Diferenciação Celular/genética , Histona Desmetilases com o Domínio Jumonji/genética , MicroRNAs/genética , Osteoblastos/metabolismo , Osteoporose/etiologia , Peptidase 7 Específica de Ubiquitina/genética , Animais , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Camundongos , Osteoblastos/citologia , Osteogênese , Osteoporose/metabolismo , Osteoporose/patologia , Transdução de Sinais , Peptidase 7 Específica de Ubiquitina/metabolismo
11.
J Am Chem Soc ; 143(2): 1038-1045, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-33405920

RESUMO

Cycloaddition reactions between oxyallyl cations and alkenes are important transformations for the construction of ring systems. Although (4 + 3) cycloaddition reactions of oxyallyl cations are well-developed, (3 + 2) cycloadditions remain rare, and an asymmetric version has not yet been developed. Moreover, because oxyallyl cations are highly electrophilic, only electron-rich olefins can be used as cycloaddition partners. We herein report a method for enantioselective (3 + 2) cycloaddition reactions between palladium-oxyallyl species and electron-deficient nitroalkenes. This transformation was enabled by a rationally designed hydrogen-bond-donating ligand (FeUrPhos) and proceeded via an inverse electron demand pathway. Using this method, we could assemble cyclopentanones with up to three contiguous stereocenters with high enantioselectivity and good to excellent diastereoselectivity.

12.
Biotechnol Appl Biochem ; 68(2): 272-278, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32275089

RESUMO

C-reactive protein (CRP) is an acute phase reactant to be a marker of inflammation and has been correlated with the cardiac injury. An immunoassay was performed using anti-human CRP antibody on an InterDigitated electrode (IDE) sensor to determine and specify CRP concentration for diagnosing the condition of myocardial inflammation. To promote the detection, gold nanoparticle (GNP) was seeded on the aminated-IDE surface. Anti-CRP was hitched on the GNP-seeded surface and identified the abundance of CRP. The limit of quantification was found as 100 fM, and the higher current response was noticed by increasing CRP concentrations with the sensitivity at 1 pM. Furthermore, CRP-spiked human serum did not interfere the determination of CRP and increased the current response, indicating suitability for a real-life sample. Similarly, the control experiments with nonimmune antibody Troponin I are not showing the definite current responses, proving the selective identification of CRP. This method of diagnosing is needful to determine the cardiovascular injury at the right time.

13.
J Hepatol ; 74(4): 838-849, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33212090

RESUMO

BACKGROUND & AIMS: Little is known about Epstein-Barr virus (EBV)-associated intrahepatic cholangiocarcinoma (EBVaICC) because of its rarity. We aimed to comprehensively investigate the clinicopathology, tumor immune microenvironment (TIME) and genomic landscape of this entity in southern China. METHODS: We evaluated 303 intrahepatic cholangiocarcinomas (ICCs) using in situ hybridization for EBV. We compared clinicopathological parameters between EBVaICC and nonEBVaICC, and we analyzed EBV infection status, tumor-infiltrating lymphocytes (TILs) and genomic features of EBVaICC by immunohistochemistry, double staining, nested PCR, multiplex immunofluorescence staining, fluorescence in situ hybridization and whole-exome sequencing. RESULTS: EBVaICC accounted for 6.6% of ICCs and was associated with EBV latency type I infection and clonal EBV isolates. Patients with EBVaICC were more often female and younger, with solitary tumors, higher HBV infection rates and less frequent cirrhosis; the lymphoepithelioma-like (LEL) subtype was more common in EBVaICC. EBVaICC was associated with a significantly larger TIME component than nonEBVaICC. The LEL subtype of EBVaICC - associated with a significantly increased density and proportion of CD20+ B cells and CD8+ T cells - was associated with significantly higher 2-year survival rates than conventional EBVaICC and nonEBVaICC. Both PD-1 and PD-L1 in TILs, and PD-L1 in tumor cells, were overexpressed in EBVaICC. High PD-L1 expression in tumor cells and high CD8+ TIL densities were significantly more common in EBVaICC than in nonEBVaICC. Seven genes (MUC4, DNAH1, GLI2, LIPE, MYH7, RP11-766F14.2 and WDR36) were mutated in at least 3 patients. EBVaICC had a different mutational pattern to liver fluke-associated cholangiocarcinoma and HBV-associated ICC. CONCLUSIONS: EBVaICC, as a subset of ICC, has unique etiological, clinicopathological and genetic characteristics, with a significantly larger TIME component. Paradoxically, patients with EBVaICC could be candidates for immune checkpoint therapy. LAY SUMMARY: Epstein-Barr virus (EBV) is associated with a subtype of intrahepatic cholangiocarcinoma, with unique clinicopathological and genetic characteristics. The tumor immune microenvironment is also different in this tumor subtype and patients with EBV-associated intrahepatic cholangiocarcinoma may respond well to immune checkpoint inhibitors.

14.
Medicine (Baltimore) ; 99(45): e22906, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33157932

RESUMO

To analyze magnetic resonance imaging features of nodular fasciitis and redefine the system for classifying this class of lesions.Twenty-seven patients with nodular fasciitis and 71 patients with other soft tissue lesions who underwent surgery or biopsy were retrospectively analysed. Demographic information, medical history, and magnetic resonance imaging features were collected. Classification of nodular fasciitis was performed based on a redefined system. Comparison between 2 groups was performed with Chi-square or Fisher exact test.For nodular fasciitis, the longest average lesion diameter was 1.87 cm (range, 0.52-5.46 cm), and 40.7% of lesions were located in the upper extremities, while 29.6% were located in the head and neck. Compared with skeletal muscle, most lesions exhibited isointensity on T1-weighted imaging and hyperintensity on T2-weighted imaging, and 45.5% of the lesions exhibited rim enhancement, 40.9% showed obvious homogenous enhancement, while 13.6% showed no enhancement or slight enhancement. The subcutaneous type accounted for 25.9% of cases, the fascial type 25.9%, the intramuscular type 29.6%, and the unclassified type 18.5%. The "fascia tail sign" was more frequently observed in nodular fasciitis than in other soft tissue lesions (P < .001). Nodular fasciitis was slightly more likely to present with the "inverted target sign" and "solar halo sign" than other soft tissue lesions (P > .05). The "cloud sign" only appeared in nodular fasciitis (P < .05).The "fascia tail sign" and "cloud sign" could help differentiate nodular fasciitis from other soft tissue lesions. A new classification may improve understanding about nodular fasciitis.


Assuntos
Fasciite/classificação , Fasciite/diagnóstico por imagem , Imageamento por Ressonância Magnética , Adolescente , Adulto , Idoso , Criança , Meios de Contraste , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
15.
Complement Ther Med ; 53: 102517, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33066854

RESUMO

BACKGROUND & OBJECTIVE: To date, cinnamon supplementation has been investigated due to its antioxidant and anti-inflammatory properties. Several studies have confirmed the effects of cinnamon supplementation on several markers of cardiometabolic health. However, the effects of cinnamon supplementation on inflammation and oxidative stress levels warrant further investigation. Hence, the current meta-analysis was conducted to elucidate the impact of cinnamon supplementation on biomarkers of inflammation and oxidative stress. METHODS: To perform this systematic review and meta-analysis, we employed the Preferred Reporting Items of Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The systematic search of available clinical trials was performed using the following databases: PubMed/MEDLINE, Scopus, Cochrane Library, Web of Science, Embase, and Google Scholar, up to January 2020. RESULTS: After removing the duplicates, 1145 studies were eligible for analysis and 12 of them were included in the meta-analysis. The dose of cinnamon powder investigated in the included trials ranged from 1.5 to 4 g/day. Cinnamon supplementation resulted in a significant reduction of C-reactive protein (CRP) (weight mean difference (WMD): -2.22 mg/L, 95 % CI: -3.74, -0.69, P = 0.004) and malondialdehyde (MDA) (WMD: -0.79 mmol/L, 95 % CI: -1.28, -0.29, P = 0.002), and marginally statistical significant decrease in interleukin-6 (IL-6) (WMD: -1.48 pg/mL, 95 % CI: -2.96, -0.01, P = 0.049). Moreover, it was associated with an increase in the total antioxidant capacity (TAC) (WMD: 0.34 mmol/L, 95 % CI: 0.04, 0.64, P = 0.026). However, the levels of intercellular adhesion molecule-1 (ICAM-1) (WMD: 1.53 ng/mL, 95 % CI: -12.03, 15.10, P = 0.82) did not change significantly following cinnamon supplementation. CONCLUSIONS: Cinnamon supplementation may be an adjuvant for reducing inflammation and oxidative stress levels in humans.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Cinnamomum zeylanicum , Suplementos Nutricionais , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Biomarcadores/sangue , Fatores de Risco Cardiometabólico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
16.
ACS Appl Mater Interfaces ; 12(39): 43444-43455, 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-32883070

RESUMO

Cisplatin resistance in tumor cells is known mainly due to the reduced accumulation of platinum ions by efflux, detoxification by intracellular GSH, and nucleotide excision repair machinery-mediated nuclear DNA repair. In this work, theranostic Pt(IV)-NPs, which are precisely self-assembled by biotin-labeled Pt(IV) prodrug derivative and cyclodextrin-functionalized IR780 in a 1:1 molecular ratio, have been developed for addressing all these hurdles via mitochondria-targeted chemotherapy solely or chemophotothermal therapy. In these nanoparticles, IR780 as a small-molecule dye acts as a mitochondria-targeting ligand to make Pt(IV)-NPs relocate finally in the mitochondria and release cisplatin. As demonstrated by in vitro and in vivo experiments, Pt(IV)-NPs can markedly facilitate cancer-specific mitochondrial targeting, inducing mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage, thus greatly increasing the Pt accumulation, reducing the GSH levels, and avoiding DNA repair machinery in cisplatin-resistant cancer cells (A549R), finally resulting in significant inhibition of A549R tumor growth on animal models by chemotherapy solely. Upon near-infrared irradiation, mitochondria-targeted chemophotothermal synergistic therapy can be realized, further overcoming cisplatin resistance and even eliminating A549R tumors completely. Moreover, such novel Pt(IV)-NPs integrate multimodal targeting (cancer and mitochondria targeting), imaging (near-infrared imaging and photoacoustic imaging), and therapeutic (chemo- and photothermal therapy) moieties in a constant ratio (1:1:1) into a single, reproducible, and structurally homogeneous entity, avoiding nonuniform drug loading and premature leakage as well as the discrete steps of imaging and therapy, which thus is more beneficial for precise therapeutics and future clinical translation.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Mitocôndrias/efeitos dos fármacos , Nanopartículas/química , Terapia Fototérmica , Pró-Fármacos/farmacologia , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Cisplatino/química , DNA Mitocondrial/efeitos dos fármacos , DNA Mitocondrial/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/metabolismo , Estrutura Molecular , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Tamanho da Partícula , Pró-Fármacos/síntese química , Pró-Fármacos/química , Propriedades de Superfície
17.
Dalton Trans ; 49(33): 11583-11590, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32766642

RESUMO

Chemotherapeutic agents that affect lysosomal functions represent a promising strategy for selective tumor therapy and overcoming drug resistance. In this work, two dinuclear phosphorescent rhenium(i) tricarbonyl complexes (DRe1 and DRe2) containing carboline derivatives have been synthesized, characterized and explored as potential chemotherapeutic and photodynamic therapy agents. The two dinuclear rhenium(i) complexes have good intrinsic phosphorescence properties and can label the lysosomes in cancer cells. Both dinuclear rhenium(i) complexes show potent anticancer activities toward several tested cancer cells. Moreover, they also have marked inhibitory activities against cisplatin-resistant human lung carcinoma cells (A549R), with complex DRe2 displaying 16-fold higher activity than cisplatin. Mechanism studies reveal that complex DRe2 can induce cancer cells to overproduce reactive oxygen species (ROS), including superoxide anion radicals, which leads to lysosomal membrane permeabilization (LMP) and subsequent cell apoptosis. Additionally, both DRe1 and DRe2 display significant phototoxicity under light (425 nm) irradiation in A549 cells, with phototoxicity index values of 60.8 and 41.8, respectively. Therefore, these two dinuclear organometallic rhenium(i) tricarbonyl complexes are potential anticancer agents for combined chemo-photodynamic therapy.


Assuntos
Antineoplásicos/síntese química , Complexos de Coordenação/síntese química , Substâncias Luminescentes/síntese química , Fármacos Fotossensibilizantes/síntese química , Rênio/química , Células A549 , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carbolinas/química , Permeabilidade da Membrana Celular , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Complexos de Coordenação/farmacologia , Descoberta de Drogas , Células HeLa , Humanos , Ligantes , Substâncias Luminescentes/farmacologia , Lisossomos/metabolismo , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
18.
Oncol Lett ; 20(4): 45, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32802167

RESUMO

In recent years, the incidence of liver cancer has increased and is currently the sixth most common tumor and the second leading cause of cancer-associated mortality worldwide. Most cases of liver cancer are hepatocellular carcinoma (HCC). Surgery, including liver transplantation or resection, and radiofrequency ablation therapies are all considered to be the curative treatment options for early-stage HCC. However, most patients have advanced HCC at the time of diagnosis, contributing to a poor prognosis. Therefore, improved treatment for late-stage HCC is needed. Immune checkpoint inhibitors (ICIs), among which programmed death receptor 1 (PD-1)/PD-ligand 1 and cytotoxic T lymphocyte-associated protein 4 are the representative immunological checkpoints, have shown great promise and progress for HCC treatment. The present review summarizes recent studies that have focused on ICIs and discusses the present limitations affecting the development of new therapeutic strategies.

19.
Angew Chem Int Ed Engl ; 59(42): 18755-18762, 2020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-32634290

RESUMO

The development and malignancy of cancer cells are closely related to the changes of the epigenome. In this work, a mitochondria-targeted rhenium(I) complex (DFX-Re3), integrating the clinical iron chelating agent deferasirox (DFX), has been designed. By relocating iron to the mitochondria and changing the key metabolic species related to epigenetic modifications, DFX-Re3 can elevate the methylation levels of histone, DNA, and RNA. As a consequence, DFX-Re3 affects the events related to apoptosis, RNA polymerases, and T-cell receptor signaling pathways. Finally, it is shown that DFX-Re3 induces immunogenic apoptotic cell death and exhibits potent antitumor activity in vivo. This study provides a new approach for the design of novel epigenetic drugs that can recode the cancer epigenome by intervening in mitochondrial metabolism and iron homeostasis.


Assuntos
Complexos de Coordenação/química , Ferro/metabolismo , Mitocôndrias/metabolismo , Rênio/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Deferasirox/química , Avaliação Pré-Clínica de Medicamentos , Epigenômica , Histonas/metabolismo , Humanos , Quelantes de Ferro/química , Metilação/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , RNA Polimerase II/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
Angew Chem Int Ed Engl ; 59(42): 18556-18562, 2020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-32557982

RESUMO

Hypoxia and the acidic microenvironment play a vital role in tumor metastasis and angiogenesis, generally compromising the chemotherapeutic efficacy. This provides a tantalizing angle for the design of platinum(IV) prodrugs for the effective and selective killing of solid tumors. Herein, two carbonic anhydrase IX (CAIX)-targeting platinum(IV) prodrugs have been developed, named as CAIXplatins. Based on their strong affinity for and inhibition of CAIX, CAIXplatins can not only overcome hypoxia and the acidic microenvironment, but also inhibit metabolic pathways of hypoxic cancer cells, resulting in a significantly enhanced therapeutic effect on hypoxic MDA-MB-231 tumors both in vitro and in vivo compared with cisplatin/oxaliplatin, accompanied with excellent anti-metastasis and anti-angiogenesis activities. Furthermore, the cancer selectivity indexes of CAIXplatins are 70-90 times higher than those of cisplatin/oxaliplatin with effectively alleviated side-effects.


Assuntos
Anidrase Carbônica IX/antagonistas & inibidores , Hipóxia Celular , Complexos de Coordenação/química , Platina/química , Pró-Fármacos/química , Animais , Anidrase Carbônica IX/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Análise por Conglomerados , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Larva/efeitos dos fármacos , Larva/metabolismo , Camundongos , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Proteoma/análise , Proteoma/efeitos dos fármacos , Proteômica , Peixe-Zebra/crescimento & desenvolvimento
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