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1.
BMC Complement Med Ther ; 20(1): 138, 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32375775

RESUMO

BACKGROUND: This is the second part of a large spectrum systematic review which aims to identify and assess the evidence for the efficacy of non-pharmacological acupuncture techniques in the treatment of chronic obstructive pulmonary disease (COPD). The results of all techniques except for filiform needle are described in this publication. METHODS: Eleven different databases were screened for randomised controlled trials up to June 2019. Authors in pairs extracted the data and assessed the risk of bias independently. RevMan 5.3 software was used for the meta-analysis. RESULTS: Thirty-three trials met the inclusion criteria, which involved the follow techniques: AcuTENS (7 trials), moxibustion (11 trials), acupressure (7 trials), ear acupuncture (6 trials), acupressure and ear acupuncture combined (1 trial) and cupping (1 trial). Due to the great heterogeneity, only 7 meta-analysis could be performed (AcuTENS vs sham on quality of life and exercise capacity, acupressure vs no acupressure on quality of life and anxiety and ear acupuncture vs sham on FEV1 and FEV1/FVC) with only acupressure showing statistical differences for quality of life (SMD: -0.63 95%CI: - 0.88, - 0.39 I2 = 0%) and anxiety (HAM-A scale MD:-4.83 95%CI: - 5.71, - 3.94 I2 = 0%). CONCLUSIONS: Overall, strong evidence in favour of any technique was not found. Acupressure could be beneficial for dyspnoea, quality of life and anxiety, but this is based on low quality trials. Further large well-designed randomised control trials are needed to elucidate the possible role of acupuncture techniques in the treatment of COPD. TRIAL REGISTRATION: PROSPERO (identifier: CRD42014015074).

2.
Expert Opin Drug Deliv ; : 1-15, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32441156

RESUMO

Introduction: Amphiphilic block copolymers are able to self-assemble into rich morphologies with high controllability for drug delivery. Great efforts have been made for decades to construct efficient drug delivery systems (DDSs) using nanostructured self-assemblies to overcome the drawbacks of pharmaceuticals, such as low aqueous solubility, premature drug release during circulation, and undesirable side effects.Areas covered: Here we review the researches of self-assembled block polymer aggregates with a focus on the shape-forming and shape-changing mechanisms, and applications of controlling morphology transition by multiple factors in drug delivery. We tend to provide a comprehensive description of the connection between structure-changing thermodynamics, kinetics, and influencing factors, thus to enlighten more pathways for future developments in the field of drug delivery.Expert opinion: By understanding the underlying mechanisms for the structure formation and transition, it enables versatile applications in DDSs design by altering drug morphologies. However, developing more sophisticated and multifunctional polymeric nanocarriers is still challengeable in the clinical application, which would hold considerable potential in promoting the efficiency in morphology control to achieve higher intelligence of drug delivery.

3.
Virus Res ; 282: 197956, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32247758

RESUMO

Porcine reproductive and respiratory syndrome virus (PRRSV) is the pathogen of porcine reproductive and respiratory syndrome (PRRS), which is one of the most economically harmful diseases in modern pig production worldwide. Receptor of activated protein C kinase 1 (RACK1) was previously shown to be indispensable for the PRRSV replication and NF-κB activation in Marc-145 cells. Here we identified a membrane protein, integrin ß3 (ITGB3), as a RACK1-interacting protein. PRRSV infection in Marc-145 cells upregulated the ITGB3 expression. Abrogation of ITGB3 by siRNA knockdown or antibody blocking inhibited PRRSV infection and NF-κB activation, while on the other hand, overexpression of ITGB3 enhanced PRRSV infection and NF-κB activation. Furthermore, inhibition of ITGB3 alleviated the cytopathic effects and reduced the TCID50 titer in Marc-145 cells. We also showed that RACK1 and ITGB3 were NF-κB target genes during PRRSV infection, and that they regulated each other. Our data indicated that ITGB3, presumably as a co-receptor, played an imperative role during PRRSV infection and NF-κB activation in Marc-145 cells. PRRSV infection activates a positive feedback loop involving the activation of NF-κB and upregulation of ITGB3 and RACK1 in Marc-145 cells. The findings would advance our elaborated understanding of the molecular host-pathogen interaction mechanisms underlying PRRSV infection in swine and suggest ITGB3 and NF-κB signaling pathway as potential therapeutic targets for PRRS control.

4.
PLoS One ; 15(4): e0231780, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32298368

RESUMO

INTRODUCTION: Little is known of acupuncture patients' experiences and opinions of clinical trials, and what may influence their compliance when participating in an acupuncture trial. OBJECTIVES: To explore the potential factors that influence patients' choice and determinants to participate in acupuncture clinical trials. METHODS: Ten qualitative, in-depth interviews were conducted with patients from acupuncture clinics in Beijing, who had previously participated in acupuncture clinical trials. RESULTS: Four main themes emerged from the interview data: effectiveness of the treatment, convenience of participating in a trial, doctor-participant communication, and participant acceptance of the treatment (or the trial). Effectiveness of acupuncture in treating the health condition was the most important factor for participant adherence. Pragmatics of treatment schedules, travel and attendance burden, together with confidence in the doctor's ability additionally influenced trial and treatment compliance. CONCLUSIONS: In-depth interviews suggest that treatment effectiveness, the pragmatics of attending treatment sessions, and the expertise and attitudes of acupuncturists are determining factors of participation and compliance in acupuncture clinical trials. Participants' confidence in, and expectation of, acupuncture may facilitate compliance, while their fear of acupuncture and negative perceptions of the trial's purpose may reduce treatment compliance. Compliance may be facilitated by enhanced doctor-patient communication, personalized treatment programs, and feedback on treatment outcomes.

5.
Dalton Trans ; 49(17): 5531-5538, 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32270143

RESUMO

Sensitive and selective quantification of specific analytes is of great significance in analytical and environmental sciences, as well as in the food industry. Herein, we report the design, synthesis, characterization, and application of a responsive ruthenium(ii) complex probe, Ru-azo, for phosphorescence and time-gated luminescence (TGL) detection of bisulfite, an important additive in the food industry. Upon a specific nucleophilic addition reaction between bisulfite and the azo group of Ru-azo, a new ruthenium(ii) complex, Ru-SO3, was obtained, which resulted in a remarkable increase in phosphorescence intensity, allowing the bisulfite detection to be achieved. In addition, long-lived emissions of Ru-azo (τ = 258 ns) and Ru-SO3 (τ = 261 ns) also enabled the TGL detection of bisulfite in autofluorescence-rich food samples. Through theoretical computations, the photoinduced electron transfer (PET) process within the ruthenium(ii) complex was validated, which unveiled the rationality of the luminescence "off-on" response of Ru-azo to bisulfite. The probe showed advantages of good water solubility, and high sensitivity, selectivity and accuracy for responding to bisulfite, facilitating its application in phosphorescence and TGL detection of bisulfite in aqueous and food samples.

6.
Int Immunopharmacol ; 84: 106504, 2020 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-32304994

RESUMO

AIM: To accumulate evidence that indicated the key role played by virus-triggered inflammation in the 2019-novel coronavirus disease (COVID-19) which emerged in Wuhan City and rapidly spread throughout China. METHODS: Age, neutrophil(NEU)-to-lymphocyte (LYM) ratio (NLR), lymphocyte-to-monocyte (MON) ratio, platelet-to-lymphocyte ratio (PLR), and C-reactive protein (CRP) of 93 patients with laboratory confirmed COVID-19 were investigated and compared. The receiver operating characteristic curve was applied to determine the thresholds for five bio-markers, and their prognostic values were assessed via the Kaplan-Meier curve and multivariate COX regression models. RESULTS: The median age was 46.4 years old, and 37cases were females. A total of 27.8% of patients had been to Wuhan, and 73.1% had contacted with people from Wuhan. Fever (83.8%) and cough (70.9%) were the two most common symptoms. Elevated NLR and age were significantly associated with illness severity. The binary logistic analysis identified elevated NLR (hazard risk [HR] 2.46, 95% confidence interval [CI] 1.98-4.57) and age (HR 2.52, 95% CI 1.65-4.83) as independent factors for poor clinical outcome of COVID-19. NLR exhibited the largest area under the curve at 0.841, with the highest specificity (63.6%) and sensitivity (88%). CONCLUSIONS: Elevated age and NLR can be considered independent biomarkers for indicating poor clinical outcomes.

7.
PLoS One ; 15(4): e0220216, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32271762

RESUMO

OBJECTIVE: To assess the relationship between opioid therapy for chronic noncancer pain and fracture risk by a meta-analysis of cohort studies and case-control studies. METHODS: The included cohort studies and case-control studies were identified by searching the PubMed and EMBASE databases from their inception until May 24, 2019. The outcome of interest was a fracture. This information was independently screened by two authors. When the heterogeneity among studies was significant, a random effects model was used to determine the overall combined risk estimate. RESULTS: In total, 12 cohort studies and 6 case-control studies were included. We used the Newcastle-Ottawa Scale (NOS) to evaluate the quality of the included literature, and 14 of the studies were considered high-quality studies. The overall relative risk of opioid therapy and fractures was 1.78 (95% confidence interval (CI) 1.53-2.07). Subgroup analyses revealed sources of heterogeneity, sensitivity analysis was stable, and no publication bias was observed. CONCLUSIONS: The meta-analysis showed that the use of opioids significantly increased the risk of fracture.

8.
Trials ; 21(1): 239, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32131886

RESUMO

BACKGROUND: Traditional Chinese medicine (TCM) usually involves syndrome differentiation and treatment. Acupuncture, one form of TCM, requires the selection of appropriate acupoints and needling techniques, but many clinical trials on acupuncture have used fixed acupuncture protocols without accounting for individual patient differences. We have designed a multicenter randomized controlled trial (RCT) to evaluate whether personalized or fixed acupuncture increases the likelihood of live births in infertile women with polycystic ovary syndrome (PCOS) compared with letrozole or placebo letrozole. We hypothesize that letrozole is more effective than personalized acupuncture, which in turn is more effective than fixed acupuncture, and that placebo letrozole is the least effective intervention. Moreover, we hypothesize that personalized acupuncture is more likely to reduce the miscarriage rate and the risk of pregnancy complications compared with letrozole. METHODS/DESIGN: The study is designed as an assessor-blinded RCT. A total of 1100 infertile women with PCOS will be recruited from 28 hospitals and randomly allocated to 4 groups: personalized acupuncture, fixed acupuncture, letrozole, or placebo letrozole. They will receive treatment for 16 weeks, and the primary outcome is live birth. Secondary outcomes include ovulation rate, conception rate, pregnancy rate, pregnancy loss rate, changes in hormonal and metabolic parameters, and changes in quality of life scores. Adverse events will be recorded throughout the trial. All statistical analyses will be performed using IBM SPSS Statistics version 21.0 software (IBM Corp., Armonk, NY, USA), and a P value < 0.05 will be considered statistically significant. DISCUSSION: This study will be the first multicenter RCT to compare the effect of personalized or fixed acupuncture with letrozole or placebo letrozole on live birth in infertile women with PCOS. The findings will inform whether personalized acupuncture therapy can be considered an alternative treatment to improve the live birth rate in infertile women with PCOS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03625531. Registered on July 13, 2018. Chinese Clinical Trial Registry, ChiCTR1800017304. Registered on July 23, 2018.

9.
J Exp Bot ; 71(9): 2740-2751, 2020 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-32053723

RESUMO

The rhizosheath is known to be beneficial for drought resistance in many plants, but the regulation of rhizosheath formation in rice plants is unclear. Here, we investigate rhizosheath formation in different rice varieties and root hair mutants. Our results showed that moderate water stress in rice induced rhizosheath formation. The soil porosity and water content were higher in the rice rhizosheath than in the rice bulk soil under moderate water stress. Additionally, rhizosheath formation in short root hair mutants was lower than in wild-type rice under moderate water stress. Moreover, transcriptomic results indicated that abscisic acid (ABA) and auxin were involved in root and root hair responses in rhizosheath formation. Further, blocking ABA and auxin pathways in wild type and in rhl1-1, the shortest root hair mutant, rhizosheath formation and root hair length were significantly decreased under moderate water stress. However, wild type plants maintained a higher root ABA content, root basipetal auxin transport, root hair length, and amount of rhizosheath than did rhl1-1. Our results suggest that moderate water stress in rice induces rhizosheath formation by modulating the ABA and auxin responses to regulate root and root hair growth, which may be used to breed rice varieties resistant to drought.

10.
Chin J Integr Med ; 26(4): 243-250, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32065348

RESUMO

OBJECTIVE: Since December 2019, an outbreak of corona virus disease 2019 (COVID-19) occurred in Wuhan, and rapidly spread to almost all parts of China. This was followed by prevention programs recommending Chinese medicine (CM) for the prevention. In order to provide evidence for CM recommendations, we reviewed ancient classics and human studies. METHODS: Historical records on prevention and treatment of infections in CM classics, clinical evidence of CM on the prevention of severe acute respiratory syndrome (SARS) and H1N1 influenza, and CM prevention programs issued by health authorities in China since the COVID-19 outbreak were retrieved from different databases and websites till 12 February, 2020. Research evidence included data from clinical trials, cohort or other population studies using CM for preventing contagious respiratory virus diseases. RESULTS: The use of CM to prevent epidemics of infectious diseases was traced back to ancient Chinese practice cited in Huangdi's Internal Classic (Huang Di Nei Jing) where preventive effects were recorded. There were 3 studies using CM for prevention of SARS and 4 studies for H1N1 influenza. None of the participants who took CM contracted SARS in the 3 studies. The infection rate of H1N1 influenza in the CM group was significantly lower than the non-CM group (relative risk 0.36, 95% confidence interval 0.24-0.52; n=4). For prevention of COVID-19, 23 provinces in China issued CM programs. The main principles of CM use were to tonify qi to protect from external pathogens, disperse wind and discharge heat, and resolve dampness. The most frequently used herbs included Radix astragali (Huangqi), Radix glycyrrhizae (Gancao), Radix saposhnikoviae (Fangfeng), Rhizoma Atractylodis Macrocephalae (Baizhu), Lonicerae Japonicae Flos (Jinyinhua), and Fructus forsythia (Lianqiao). CONCLUSIONS: Based on historical records and human evidence of SARS and H1N1 influenza prevention, Chinese herbal formula could be an alternative approach for prevention of COVID-19 in high-risk population. Prospective, rigorous population studies are warranted to confirm the potential preventive effect of CM.


Assuntos
Betacoronavirus , Infecções por Coronavirus/terapia , Medicamentos de Ervas Chinesas/uso terapêutico , Epidemias , Medicina Tradicional Chinesa , Pneumonia Viral/terapia , Ensaios Clínicos como Assunto , Infecções por Coronavirus/tratamento farmacológico , Epidemias/história , Epidemias/prevenção & controle , História Antiga , Humanos , Controle de Infecções/história , Controle de Infecções/métodos , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/terapia , Medicina Tradicional Chinesa/história , Medicina Tradicional Chinesa/métodos , Pandemias , Qi , Síndrome Respiratória Aguda Grave/terapia
11.
Adv Healthc Mater ; 9(6): e1901706, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32052565

RESUMO

Preventing cancer metastasis is one of the remaining challenges in cancer therapy. As an efficient natural product, alpha-tocopheryl succinate (α-TOS), the most effective form of vitamin E, holds great anticancer potential. To improve its efficacy and bioavailability, lipid-coated calcium carbonate/phosphate (LCCP) nanoparticles (NPs) with folic acid and PEG modification are synthesized for efficient delivery of α-TOS to 4T1 cancer cells. The optimized LCCP-FA NPs (NP-TOS15) show an α-TOS loading efficiency of around 60%, and enhanced uptake by 4T1 metastatic cancer cells. Consequently, NP-TOS15 significantly enhance the anticancer effect in combination with interferon-gamma (IFN-γ) in terms of apoptosis facilitation and migration inhibition. Importantly, NP-TOS15 upregulate the anticancer immunity via downregulating program death ligand 1 (PD-L1) expression that is initially induced by IFN-γ, and remarkably prevent the lung metastasis, particularly in combination with IFN-γ. Further investigation reveals that this combination therapy also modulates the cytotoxic lymphocyte infiltration into the tumor microenvironment for tumor elimination. Taken together, the NP delivery of α-TOS in combination with IFN-γ provides an applicable strategy for cancer therapy.

12.
Curr Neurovasc Res ; 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32056526

RESUMO

OBJECTIVE: The effects of mesenchymal stem cell (MSC)-derived exosomes on brain microvascular endothelial cells under oxygen-glucose deprivation (OGD), which mimics cells in deep hypothermic circulatory arrest (DHCA) in vitro, are yet to be studied. METHODS: MSCs were co-cultured with primary rat brain endothelial cells, which were then exposed to OGD. Cell viability, apoptosis, the inflammatory factors (IL-1ß, IL-6, and TNF-α), and the activation of inflammation-associated TLR4-mediated pyroptosis and the NF-κB signaling pathway were determined. Furthermore, exosomes derived from MSCs were isolated and incubated with endothelial cells to investigate whether the effect of MSCs is associated with MSC-derived exosomes. Apoptosis, cell viability, and the inflammatory response were also analyzed in OGD-induced endothelial cells incubated with MSC-derived exosomes. RESULTS: OGD treatment promoted endothelial cell apoptosis, induced the release of inflammatory factors IL-1ß, IL-6, and TNF-α, and inhibited cell viability. Western blot analysis showed that OGD treatment induced TLR4, and NF-κB p65 subunit phosphorylation and caspase-1 upregulation, while co-culture with MSCs could reduce the effect of OGD treatment on endothelial cells. As expected, the effect of MSC-derived exosomes on OGD-treated endothelial cells was similar to that of MSCs. MSC-derived exosomes alleviated the OGD-induced decrease in the viability of endothelial cells, and increased levels of apoptosis, inflammatory factors, and the activation of inflammatory and inflammatory focal pathways. CONCLUSION: Both MSCs and MSC-derived exosomes attenuated OGD-induced rat primary brain endothelial cell injury. These findings suggest that at least some of the protective effects of MSCs on endothelial cells are mediated by MSC-derived exosomes.

13.
Sensors (Basel) ; 20(4)2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32059556

RESUMO

Capacitive transducers are widely used in fundamental physics experiments, seismology, Earth or planetary observations, and space scientific and technical applications because of their high precision, simple structure, and compatibility with various measurements. However, in real applications, there is a trade-off between their resolution and dynamic range. Therefore, this paper is aimed at enlarging the dynamic range while ensuring high resolution. In this paper, a noise analysis of a capacitive transducer is presented, which shows that the amplitude noise of the carrier wave is the main limiting factor. Hence, a new method of generating a carrier wave with lower-amplitude noise is proposed in the paper. Based on the experimental verification, it is found that the carrier wave produced through the new method performed significantly better than the typical digital carrier wave when they were compared in the same sensing circuit. With the carrier wave produced through the new method, the dynamic range of the capacitive transducer can reach 120.7 dB, which is 18.3 dB greater than for the typical direct digital synthesis (DDS) method. In addition, the resolution of the carrier wave is mainly limited by the voltage reference components.

14.
Anal Chim Acta ; 1103: 156-163, 2020 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-32081180

RESUMO

Gasotransmitter hydrogen sulfide (H2S), produced enzymatically in body, has important functions in biological signaling and metabolic processes. An abnormal level of H2S expression is associated with different diseases, therefore, development of novel bioanalytical methods for rapid and effective detection of H2S in biological conditions is of great importance. In this work, we report the development of a new responsive nanosensor for ratiometric luminescence detection of H2S in aqueous solution and live cells. The nanosensor (Ru@FITC-MSN) was prepared by immobilizing a luminescent ruthenium(II) (Ru(II)) complex into a fluorescein isothiocyanate (FITC) conjugated water-dispersible mesoporous silica nanoparticle (MSN), showing dual emission bands at 520 nm (FITC) and 600 nm (Ru complex). The red luminescence of the formed Ru@FITC-MSN was quenched in the presence of Cu2+. The in-situ generated Ru-Cu@FITC-MSN responded to H2S rapidly and selectively, showing a linear ratiometric luminescence change in FITC and Ru(II) channels with the H2S concentration (0.5-4 µM). Limit of detection (LoD) and limit of quantification (LoQ) were determined to be 0.36 and 1.21 µM. Followed by investigation of cellular uptake processes, the utility of the nanosensor for ratiometric imaging of H2S in live cells and its capability to monitor H2S levels in inflammatory breast cancer cells were then demonstrated. This study provides a powerful approach for detection of highly reactive and unstable H2S biomolecules in live systems.

15.
Sensors (Basel) ; 20(1)2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31948044

RESUMO

The Coriolis Vibratory Gyroscopes are a type of sensors that measure angular velocities through the Coriolis effect. The resonator is the critical component of the CVGs, the vibrational characteristics of which, including the resonant frequency, frequency mismatch, Q factor, and Q factor asymmetry, have a great influence on the performance of CVG. The frequency mismatch and Q factor of the resonator, in particular, directly determine the precision and drift characteristics of the gyroscope. Although the frequency mismatch and Q factor are natural properties of the resonator, they can change with external conditions, such as temperature, pressure, and external forces. In this paper, the influence of electrostatic forces on the vibrational characteristics of the fused silica cylindrical resonator is investigated. Experiments were performed on a fused silica cylindrical resonator coated with Cr/Au films. It was shown that the resonant frequency, frequency mismatch, and the decay time slightly decreased with electrostatic forces, while the decay time split increased. Lower capacitive gaps and larger applied voltages resulted in lower frequency mismatch and lower decay time. This phenomenon was theoretically analyzed, and the variation trends of results were consistent with the theoretical analysis. This study indicates that, for fused silica cylindrical resonator with electrostatic transduction, the electrostatic influence on the Q factor and frequency, although small, should be considered when designing the capacitive gap and choosing bias voltages.

16.
Behav Processes ; 171: 104029, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31899274

RESUMO

Nest predation often leads to breeding failure and is an important component of natural selection that affects the evolution of nest defense behavior in birds. Many tit species give a hissing call as nest defense, but there are few studies of interspecific variation in hissing calls, and whether these are related to nest predation and nesting success. In this study, we compared the hissing calls of five tit species including cinereous tits (Parus cinereus), marsh tits (Poecile palustris), varied tits (Sittiparus varius), willow tits (Poecile montanus), and coal tits (Periparus ater) in Saihanba National Forest Park in Hebei and Xianrendong National Nature Reserve in Liaoning. In Saihanba of Hebei, the proportion of cinereous, willow, and coal tit individuals giving a hissing call differed significantly but the rate of nest predation was similar. It was also true for the three tit species (cinereous, varied, and marsh tits) in Xianrendong of Liaoning. Cinereous and varied tits showed no differences in clutch size, date of the first egg, nest predation and nesting success between individuals that gave and those that did not give a hissing call. These results indicate that for tit species that breed in nest boxes distributed within the same area, there is interspecific variation in hissing calls but this variation is not significantly correlated with nest predation risk.

17.
J Mater Chem B ; 8(7): 1496-1506, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31999290

RESUMO

Targeting drug delivery to macrophage/foam cells is challenged owing to the poor cell permeability and fluidity resulting from the massive accumulation of intracellular cholesterol in atherosclerosis (AS). Discoidal reconstituted high-density lipoprotein (d-rHDL) has been well regarded as a potential drug delivery system for AS by virtue of its plaque-targeting and cholesterol removal abilities, while the latter is compromised by the high activation energy of cholesterol efflux. It is reported that a low concentration of ß-cyclodextrin (ß-CD) can function as a cholesterol shuttle to promote cholesterol efflux from cells to the extracellular acceptors (cholesterol sink, such as HDL particles), but it is still unknown whether the combination of ß-CD with a drug-loaded d-rHDL can function as a shuttle/sink model to promote the remodeling and drug release of the d-rHDL carrier after accelerating the cholesterol efflux. Furthermore, it is interesting to investigate whether enhanced cholesterol efflux can improve the cellular drug uptake by restoring the permeability and fluidity of the cell membrane. Here, simvastatin-loaded d-rHDL (ST-d-rHDL) was combined with different concentrations of ß-CD. Compared with ST-d-rHDL alone, the cholesterol removal ability of ST-d-rHDL combined with 0.5 mM of ß-CD increased by 31-fold after incubation for 6 h and the cumulative drug release of ST-d-rHDL increased by two-fold during the initial 1 h in an acellular mimetic system. In macrophage/foam cells, 0.5 mM of ß-CD showed superior promoting effects in the cholesterol removal ability and remodeling of ST-d-rHDL compared to 0.1 mM of ß-CD. The high concentration of ß-CD at 2 mM displayed a low efficiency for accelerating cholesterol efflux, which might function as a cholesterol sink rather than a cholesterol shuttle. Moreover, the permeability and fluidity of the cell membrane were improved by combining 0.5 mM of ß-CD with ST-d-rHDL, which exhibited an enhanced cellular drug uptake and inhibiting effect on the intracellular lipid deposition and secretion of inflammatory cytokine. Collectively, combination of ß-CD and ST-d-rHDL as a shuttle/sink model could enhance cholesterol efflux and drug uptake to suppress inflammation in macrophage/foam cells.

18.
J Control Release ; 320: 142-158, 2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-31978442

RESUMO

The conventional active-targeting nano-chemotherapy suffers from poor tumor tissue penetration and non-negligible toxicity due to the size/ligand dilemmas and insufficient target selectivity. In this report, a stimuli-responsive size-adaptable and ligand (biotin)-sheddable drug delivery system (DDS) combined with two-step strategy of biotin-avidin system was designed to seek a balance between tumor targeting and penetration as well as to self-scavenge the nonresponsive nanocarriers in normal tissues. This DDS was composed of 'multi-seed' polymeric liposomes (ASL-BIO-MPL) with asulacrine-loaded micelles as seeds in their aqueous cavities. The shell of such liposomes was modified with MMP-9 cleavable polymer-polypeptide functionalized with the tumor targeting ligand biotin. ASL-BIO-MPL could disintegrate into mixture of irregularly-shaped liposomes (~200 nm) and scattered tiny micelles (~40 nm) after incubation with MMP-9. The fluorescence-labeled BIO-MPL could travel to the center of the 4T1 breast tumor spheroids under the action of MMP-9, possibly benefited from the relay of released tiny micelles. Conversely, neither the biotin-modified micelles nor non-MMP-9-responsive multi-seed liposomes could penetrate into the spheroids possibly due to the potent binding-site barrier of biotin and large size, respectively. In tumor-bearing mice, ASL-BIO-MPL exhibited the strongest drug penetrability and thus the optimal inhibition of tumor growth compared to other formulations. Following administration of avidin with a rational dosage regimen, the number of apoptotic cells in normal tissues induced by ASL-BIO-MPL reduced without affecting their targeting effect, suggesting the followed administration of adivin could scavenge the DDS in non-target site. Overall, the size/ligand adapting MPL system combined with two-step strategy of biotin-avidin may provide potential avenues for nanocarriers to enhance deep tumor tissue targeting and protect normal tissues.

19.
Biochem Biophys Res Commun ; 521(1): 232-237, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31653348

RESUMO

The use of highly efficient high-throughput screening (HTS) platform has recently gained more attention as a plausible approach to identify de novo therapeutic application potential of conventional anti-tumor drugs for cancer treatments. In this study, we used hepatocellular carcinoma (HCC) cells as models to identify cytotoxic compounds by HTS. To identify cytotoxic compounds for potential HCC treatments, 3271 compounds from three well established small molecule libraries were screened against HCC cell lines. Thirty-two small molecules were identified from the primary screen to induce cell death. Particularly, mitoxantrone (MTX), which is an established antineoplastic drug, significantly and specifically inhibited the growth and proliferation of HCC cells in vitro. Mechanistic studies of LC3-II, p62 and phosphorylation of p70S6K in HepG2 cells revealed that MTX treatment induced mTOR-dependent autophagy activation, which was further confirmed by the autophagic flux assay using lysosomal inhibitor chloroquine (CQ). In the combined treatment of MTX and CQ, where autophagy was inhibited by CQ, the elevations of cleaved Caspase-3 and PARP were observed, indicating the enhanced apoptosis in HepG2 cells. Taken together, we hypothesize that MTX-induced autophagy plays an pro-survival role in HCC treatment. Combined treatment with autophagy inhibitor may combat the chemo-resistance of HCC to MTX treatment and therefore deserves future clinical investment.

20.
Neurol Sci ; 41(3): 661-667, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31754876

RESUMO

As a noninvasive technique, transcranial sonography (TCS) of substantia nigra (SN) has gradually showed its effectiveness not only in diagnosis but also in understanding clinical features of Parkinson's Disease (PD). This study aimed to further evaluate TCS for clinical diagnosis of PD, and to explore the association between sonographic manifestations and visual hallucinations (VH). A total of 226 subjects including 141 PD patients and 85 controls were recruited. All participants received TCS. A series of rating scales to evaluate motor and non-motor symptoms were performed in PD patients. Results showed that 172 subjects were successfully assessed by TCS. The area of SN was greater in PD patients than that in controls (P < 0.001). As receiver-operating characteristic (ROC) curve analysis showed, the best cutoff value for the larger SN echogenicity size was 23.5 mm2 (sensitivity 70.3%, specificity 77.0%). Patients with VH had larger SN area (P = 0.019), as well as higher Non-Motor Symptoms Scale (NMSS) scores (P = 0.018). Moreover, binary logistic regression analysis indicated that SN hyperechogenicity (odds ratio = 4.227, P = 0.012) and NMSS scores (odds ratio = 0.027, P = 0.042) could be the independent predictors for VH. In conclusion, TCS can be used as an auxiliary diagnostic tool for Parkinson's disease. Increased SN echogenicity is correlated with VH in Parkinson's disease, possibly because the brain stem is involved in the mechanism in the onset of VH. Further studies are needed to confirm these findings.

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