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1.
Heliyon ; 10(12): e32351, 2024 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-38988534

RESUMEN

Chronic obstructive pulmonary disease (COPD) is a respiratory inflammatory disease. Psoralen (PSO) is the main pharmacological component identified from Bu-Shen-Fang-Chuan formula which has been traditionally used in treatment of COPD, yet its efficacy in COPD inflammation were unreported. In this study, we aimed to elucidate the anti-inflammatory potential of PSO in COPD and unravel the underlying mechanisms, focusing on T lymphocyte recruitment and the modulation of chemokines, namely monokine induced by interferon-gamma (CXCL9), interferon inducible protein 10 (CXCL10), and interferon inducible T-Cell alpha chemoattractant (CXCL11). In vitro, RAW264.7 was stimulated by interferon (IFN)-γ + cigarette smoke extract (CSE) and were treated with PSO (2.5, 5, 10 µM), then the levels of chemokines and the activation of Janus kinase (JAK)/Signal transducer and activator of transcription 1 (STAT1) pathway were analyzed by real time PCR and western blot. In vivo, a murine model was established by intraperitoneal injection of CSE on day 1, 8, 15, and 22, then treated with PSO (10 mg/kg). Our experiments in vitro illustrated that PSO reduced the levels of CXCL9, CXCL10, and CXCL11, and decreased the protein phosphorylation levels of JAK2 and STAT1. Additionally, PSO effectively improved inflammatory infiltration and decreased the proportion of CD8+ T cells in CSE-exposed mice. Furthermore, PSO reduced the levels of CXCL9, CXCL10, and CXCL11 in bronchoalveolar lavage fluid (BALF) and lung tissue, and decreased the protein phosphorylation levels of JAK2 and STAT1. In conclusion, our results revealed the therapeutic potential of PSO for COPD inflammation, possibly mediated through the regulation of CD8+ T cell recruitment and chemokines via the JAK2/STAT1 signaling pathway.

2.
Nutrients ; 16(5)2024 Feb 29.
Artículo en Inglés | MEDLINE | ID: mdl-38474843

RESUMEN

Cholesterol is a nutrient commonly found in the human diet. The relationship between dietary cholesterol, its sources, and cardiovascular disease (CVD) is still a topic of debate. This study aimed to investigate the association between dietary cholesterol, its sources, and cardiovascular events in a Chinese population. The present study analyzed data from the China Health and Nutrition Survey (CHNS) cohort between 1991 and 2015. This study analyzed data from 3903 participants who were 40 years of age or older at baseline and had no history of cardiovascular disease, diabetes, or hypertension. During a median follow-up of 14 years, 503 cardiovascular disease events were identified through follow-up questionnaires administered every 2-3 years. The events included fatal and nonfatal coronary heart disease, stroke, heart failure, and other cardiovascular disease deaths. Cox regression was used to estimate risk ratios (HR) for CVD events after adjusting for demographic, socioeconomic, and behavioral factors. It was discovered that sources of dietary cholesterol varied among different subgroups of the population. The top three sources of cholesterol among all participants were eggs, red meat, and seafood, accounting for 57.4%, 28.2%, and 9.0% of total daily cholesterol intake, respectively. The present study found that there was a significant association between total dietary cholesterol intake, and the risk of developing cardiovascular disease (adjusted HR [95% CI]: total cholesterol (highest and lowest quartiles compared) 1.57 [1.17-2.11]). Cholesterol from poultry, seafood, and eggs was also significantly associated with a reduced risk of CVD (adjusted HR [95% CI]: poultry 0.18 [0.04-0.82], seafood 0.11 [0.02-0.54], and eggs 0.16 [0.03-0.73]). After adjusting for daily caloric intake, daily fat intake, and daily saturated fat intake, the previously observed association between red meat cholesterol and cardiovascular events (unadjusted HR [95% CI]: 0.44 [0.35-0.55]) was no longer statistically significant (adjusted HR [95% CI]: 0.21 [0.04-1.01]).


Asunto(s)
Enfermedades Cardiovasculares , Humanos , Enfermedades Cardiovasculares/epidemiología , Colesterol en la Dieta , Dieta , Colesterol , Ingestión de Alimentos , Factores de Riesgo
3.
Expert Opin Drug Deliv ; 20(12): 1749-1767, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37905998

RESUMEN

INTRODUCTION: Brain cancer is a debilitating disease with a poor survival rate. There are significant challenges for effective treatment due to the presence of the blood-brain barrier (BBB) and blood-tumor barrier (BTB) which impedes drug delivery to tumor sites. Many nanomedicines have been tested in improving both the survival and quality of life of patients with brain cancer with the recent focus on inorganic nanoparticles such as silica nanoparticles (SNPs). This review examines the use of SNPs as a novel approach for diagnosing, treating, and theranostics of brain cancer. AREAS COVERED: The review provides an overview of different brain cancers and current therapies available. A special focus on the key functional properties of SNPs is discussed which makes them an attractive material in the field of onco-nanomedicine. Strategies to overcome the BBB using SNPs are analyzed. Furthermore, recent advancements in active targeting, combination therapies, and innovative nanotherapeutics utilizing SNPs are discussed. Safety considerations, toxicity profiles, and regulatory aspects are addressed to provide an understanding of SNPs' translational potential. EXPERT OPINION: SNPs have tremendous prospects in brain cancer research. The multifunctionality of SNPs has the potential to overcome both the BBB and BTB limitations and can be used for brain cancer imaging, drug delivery, and theranostics. The insights provided will facilitate the development of next-generation, innovative strategies, guiding future research toward improved diagnosis, targeted therapy, and better outcomes in brain cancer patients.


Asunto(s)
Neoplasias Encefálicas , Nanopartículas , Humanos , Calidad de Vida , Encéfalo , Barrera Hematoencefálica , Neoplasias Encefálicas/tratamiento farmacológico , Nanomedicina/métodos , Sistemas de Liberación de Medicamentos/métodos
4.
J Mater Chem B ; 12(1): 97-111, 2023 12 22.
Artículo en Inglés | MEDLINE | ID: mdl-37842835

RESUMEN

3D printing of titanium (Ti) metal has potential to transform the field of personalised orthopaedics and dental implants. However, the impacts of controlled surface topographical features of 3D printed Ti implants on their interactions with the cellular microenvironment and incorporation of biological growth factors, which are critical in guiding the integration of implants with bone, are not well studied. In the present study, we explore the role of surface topological features of 3D printed Ti implants using an anodised titania nanotube (TiNT) surface layer in guiding their immune cell interaction and ability to deliver bioactive form of growth factors. TiNT layers with precisely controlled pore diameter (between 21and 130 nm) were anodically grown on 3D printed Ti surfaces to impart a nano-micro rough topology. Immune biomarker profiles at gene and protein levels show that anodised 3D Ti surfaces with smaller pores resulted in classical activation of macrophages (M1-like), while larger pores (i.e., >100 nm) promoted alternate activation of macrophages (M2-like). The in vitro bone mineralisation studies using the conditioned media from the immunomodulatory studies elucidate a clear impact of pore diameter on bone mineralisation. The tubular structure of TiNTs was utilised as a container to incorporate recombinant human bone morphogenetic protein-2 (BMP-2) in the presence of various sugar and polymeric cryoprotectants. Sucrose offered the most sustainable release of preserved BMP-2 from TiNTs. Downstream effects of released BMP-2 on macrophages as well as bone mineralisation were assessed showing bioactivity retention of the released rhBMP-2. Overall, the TiNT surface topography in combination with controlled, sustained, and local release of bioactive growth factors can potentially enhance the osseointegration outcomes of custom 3D printed Ti implants in the clinic.


Asunto(s)
Regeneración Ósea , Titanio , Humanos , Titanio/farmacología , Titanio/química , Propiedades de Superficie , Impresión Tridimensional
5.
Adv Drug Deliv Rev ; 203: 115115, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37844843

RESUMEN

Silica nanoparticles (SNP) have gained tremendous attention in the recent decades. They have been used in many different biomedical fields including diagnosis, biosensing and drug delivery. Medical uses of SNP for anti-cancer, anti-microbial and theranostic applications are especially prominent due to their exceptional performance to deliver many different small molecules and recently biologics (mRNA, siRNA, antigens, antibodies, proteins, and peptides) at targeted sites. The physical and chemical properties of SNP such as large specific surface area, tuneable particle size and porosity, excellent biodegradability and biocompatibility make them an ideal drug delivery and diagnostic platform. Based on the available data and the pre-clinical performance of SNP, recent interest has driven these innovative materials towards clinical application with many of the formulations already in Phase I and Phase II trials. Herein, the progress of SNP in biomedical field is reviewed, and their safety aspects are analysed. Importantly, we critically evaluate the key structural characteristics of SNP to overcome different biological barriers including the blood-brain barrier (BBB), skin, tumour barrier and mucosal barrier. Future directions, potential pathways, and target areas towards rapid clinical translation of SNP are also recommended.


Asunto(s)
Nanopartículas , Neoplasias , Humanos , Portadores de Fármacos/química , Dióxido de Silicio , Sistemas de Liberación de Medicamentos , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Porosidad
6.
Pharmaceutics ; 15(9)2023 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-37765208

RESUMEN

The presence of the blood-brain barrier (BBB) limits the delivery of therapies into the brain. There has been significant interest in overcoming the BBB for the effective delivery of therapies to the brain. Inorganic nanomaterials, especially silica nanoparticles with varying surface chemistry and surface topology, have been recently used as permeation enhancers for oral protein delivery. In this context, nanoparticles with varying sizes and surface chemistries have been employed to overcome this barrier; however, there is no report examining the effect of nanoscale roughness on BBB permeability. This paper reports the influence of nanoscale surface roughness on the integrity and permeability of the BBB in vitro, using smooth surface Stöber silica nanoparticles (60 nm) compared to rough surface virus-like silica nanoparticles (VSNP, 60 nm). Our findings reveal that VSNP (1 mg/mL) with virus-mimicking-topology spiky surface have a greater effect on transiently opening endothelial tight junctions of the BBB than the same dose of Stöber silica nanoparticles (1 mg/mL) by increasing the FITC-Dextran (70 kDa) permeability 1.9-fold and by decreasing the trans-endothelial electrical resistance (TEER) by 2.7-fold. This proof-of-concept research paves the way for future studies to develop next-generation tailored surface-modified silica nanoparticles, enabling safe and efficient macromolecule transport across the BBB.

7.
Int J Pharm ; 642: 123132, 2023 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-37315638

RESUMEN

Through 3D printing (3DP), many parameters of solid oral dosage forms can be customised, allowing for truly personalised medicine in a way that traditional pharmaceutical manufacturing would struggle to achieve. One of the many options for customisation involves dose titration, allowing for gradual weaning of a medication at dose intervals smaller than what is available commercially. In this study we demonstrate the high accuracy and precision of 3DP dose titration of caffeine, selected due to its global prevalence as a behavioural drug and well-known titration-dependent adverse reactions in humans. This was achieved using a simple filament base of polyvinyl alcohol, glycerol, and starch, utilising hot melt extrusion coupled with fused deposition modelling 3DP. Tablets containing 25 mg, 50 mg, and 100 mg doses of caffeine were successfully printed with drug content in the accepted range prescribed for conventional tablets (90 - 110%), and excellent precision whereby the weights of all doses showed a relative standard deviation of no more than 3%. Importantly, these results proved 3D printed tablets to be far superior to splitting a commercially available caffeine tablet. Additional assessment of filament and tablet samples were reviewed by differential scanning calorimetry, thermogravimetric analysis, HPLC, and scanning electron microscopy, showing no evidence of degradation of caffeine or the raw materials, with smooth and consistent filament extrusion. Upon dissolution, all tablets achieved greater than 70% release between 50 and 60 min, showing a predictable rapid release profile regardless of dose. The outcomes of this study highlight the benefits that dose titration with 3DP can offer, especially to more commonly prescribed medications that can have even more harmful withdrawal-induced adverse reactions.


Asunto(s)
Cafeína , Alcohol Polivinílico , Humanos , Cafeína/química , Comprimidos/química , Alcohol Polivinílico/química , Tecnología de Extrusión de Fusión en Caliente , Impresión Tridimensional , Liberación de Fármacos , Tecnología Farmacéutica/métodos
8.
Biomater Sci ; 11(13): 4508-4521, 2023 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-37248862

RESUMEN

Nanoparticle based permeation enhancers have the potential to improve the oral delivery of biologics. Recently, solid silica nanoparticles were discovered to improve the intestinal permeability of peptides and proteins via transient opening of the gut epithelium. In this study, we have developed small-sized (∼60 nm) virus-like silica nanoparticles (VSNP) as a reversible and next generation non-toxic permeation enhancer for oral delivery of biologics. Our results show that the anionic VSNP showed a better permeation-enhancing effect than the same sized spherical Stöber silica nanoparticles (∼60 nm) by enhancing the apparent insulin permeability by 1.3-fold in the Caco-2 monolayer model and by 1.2-fold in the Caco-2/MTX-HT-29 co-culture model. In vivo experiments in healthy mice demonstrated that anionic VSNP significantly enhanced the permeation of fluorescently labelled 4 kDa dextran after oral administration compared to Stöber nanoparticles and positively charged VSNP. The results indicated that the nanoscale surface roughness is an important consideration when designing nanoparticle-based permeation enhancers. Overall, our study shows for the first time that small-sized (∼60 nm) VSNP with nanoscale surface roughness can be used as a non-toxic permeation enhancer for oral delivery of therapeutic peptides and proteins.


Asunto(s)
Nanopartículas , Dióxido de Silicio , Humanos , Ratones , Animales , Células CACO-2 , Dióxido de Silicio/metabolismo , Mucosa Intestinal/metabolismo , Péptidos/química , Administración Oral , Nanopartículas/química
9.
Mol Pharm ; 20(6): 2966-2977, 2023 06 05.
Artículo en Inglés | MEDLINE | ID: mdl-37216314

RESUMEN

Coenzyme Q10 is a potent antioxidant that plays an important role in the maintenance of various biochemical pathways of the body and has a wide range of therapeutic applications. However, it has low aqueous solubility and oral bioavailability. Mesoporous silica nanoparticles (MCM-41 and SBA-15 types) exhibiting varying pore sizes and modified with phosphonate and amino groups were used to study the influence of pore structure and surface chemistry on the solubility, in vitro release profile, and intracellular ROS inhibition activity of coenzyme Q10. The particles were thoroughly characterized to confirm the morphology, size, pore profile, functionalization, and drug loading. Surface modification with phosphonate functional groups was found to have the strongest impact on the solubility enhancement of coenzyme Q10 when compared to that of pristine and amino-modified particles. Phosphonate-modified MCM-41 nanoparticles (i.e., MCM-41-PO3) induced significantly higher coenzyme Q10 solubility than the other particles studied. Furthermore, MCM-41-PO3 led to a twofold decrease in ROS generation in human chondrocyte cells (C28/I2), compared to the free drug in a DMSO/DMEM mixture. The results confirmed the significant contribution of small pore size and negative surface charge of MSNs that enable coenzyme Q10 confinement to allow enhanced drug solubility and antioxidant activity.


Asunto(s)
Antioxidantes , Nanopartículas , Humanos , Solubilidad , Antioxidantes/farmacología , Especies Reactivas de Oxígeno , Nanopartículas/química , Dióxido de Silicio/química , Porosidad , Portadores de Fármacos/química
10.
J Control Release ; 357: 161-174, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36965857

RESUMEN

The prognosis of brain cancers such as glioblastoma remains poor despite numerous advancements in the field of neuro-oncology. The presence of the blood brain barrier (BBB) along with the highly invasive and aggressive nature of glioblastoma presents a difficult challenge for developing effective therapies. Temozolomide (TMZ) is a first line agent used in the clinic for glioblastoma and it has been useful in increasing patient survival rates. However, TMZ suffers from issues related to its pharmacokinetics, such as a short plasma half-life (2 h), is subjected to P-gp efflux, and has limited extravasation from blood to brain (∼20%). It has been postulated that reducing its efflux and increasing glioblastoma tissue exposure to TMZ could prove useful in treating glioblastoma and preventing tumour recurrence. Herein, ultra-small, large pore silica nanoparticles (USLP) have been loaded with TMZ, surface PEGlyated to reduce efflux and decorated with the cascade targeting protein lactoferrin for efficient uptake across the BBB and into glioblastoma. Our results demonstrate that USLP improves permeability of BBB in vitro as evidenced using a transwell model which mimics endothelial tight junctions with permeation being enhanced using PEGylated particles. Data from TMZ loaded USLP in vitro transwell BBB model also suggests that the USLP formulations can significantly reduce the efflux ratio of TMZ. In vitro apoptosis studies on glioblastoma cell lines U87 and GL261 were conducted which showed an improvement in TMZ induced glioblastoma apoptosis with USLP formulations compared to pure TMZ. Finally, a proof-of-concept preclinical mouse study demonstrated that when given intravenously at 50 mg/kg, USLP particles showed accumulation in the brain within a few hours without any obvious pathophysiological changes in vital organs as assessed via histology. Overall, the data suggests our innovative delivery system is efficient in extravasation from blood and permeating the BBB and has potential to improve efficacy of TMZ in glioblastoma therapy.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Nanopartículas , Ratones , Animales , Temozolomida/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Línea Celular Tumoral , Encéfalo/patología , Nanopartículas/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Antineoplásicos Alquilantes
11.
Oxid Med Cell Longev ; 2023: 4144138, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36814956

RESUMEN

Background: Studies that looked at asthma airway remodeling pathogenesis and prevention have led to the discovery of the rat sarcoma viral oncogene (RAS) signaling pathway as a key mechanism that controls airway smooth muscle cell (ASMC) proliferation. Baicalin has great anti-inflammatory, proliferation-inhibited, and respiratory disease-relieving properties. However, the inhibitory effects and mechanisms of baicalin on ASMC-mediated airway remodeling in mice are still poorly understood. Methods: After establishing the asthmatic mice model by ovalbumin (OVA) and interfering with baicalin, airway remodeling characteristics such as airway resistance, mRNA, and protein expression levels of remodeling-related cytokines were measured by histopathological assessment, quantitative real-time polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), and western blot. Further efforts on detailed mechanisms were used antibody arrays to compare the expression and activation of proteins involved in the RAS signaling pathway. In addition, validation experiments were performed in ASMC proliferation model and low-expression cells of the target gene by using shRNA. Results: In OVA-induced asthmatic mice model, baicalin significantly reduced the infiltration of inflammatory cells in lung tissue, attenuated airway resistance, and decreased mRNA and protein expression levels of remodeling-related cytokines such as interleukin-13 (IL-13), vascular endothelial growth factor (VEGF), transforming growth factor-beta 1 (TGF-ß1), matrix metallopeptidase 9 (MMP9), and tissue inhibitor of metalloproteinase 1 (TIMP1). The results of antibody arrays involved in RAS signaling pathway revealed that OVA and baicalin administration altered the activation of protein kinase C alpha type (PKC-α), A-rapidly accelerated fibrosarcoma (A-RAF), mitogen-activated protein kinase 2 (MEK2), extracellular regulated MAP kinase (ERK), MAPK interacting serine/threonine kinase 1 (MNK1), and ETS transcription factor 1 (ELK1). The above results were further verified in the ASMC proliferation model. A-RAF silencing (shA-RAF) could promote ASMC proliferation and downregulate p-MEK2, p-ERK, p-MNK1, and p-ELK1 expression. Conclusion: The effects of baicalin against airway remodeling and ASMC proliferation might partially be achieved by suppressing the RAS signaling pathway. Baicalin may be a new therapeutic option for managing airway remodeling in asthma patients.


Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias) , Asma , Animales , Ratones , Factor A de Crecimiento Endotelial Vascular/metabolismo , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Asma/tratamiento farmacológico , Transducción de Señal , Pulmón/patología , Citocinas/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Miocitos del Músculo Liso/metabolismo , Proliferación Celular , ARN Mensajero/metabolismo
12.
Pharmaceutics ; 14(11)2022 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-36365121

RESUMEN

Micro-ribonucleic acid (miRNA)-based therapies show advantages for bone regeneration but need efficient intracellular delivery methods. Inorganic nanoparticles such as mesoporous bioactive glass nanoparticles (MBGN) and mesoporous silica nanoparticles (MSN) have received growing interest in the intracellular delivery of nucleic acids. This study explores the capacity of MBGN and MSN for delivering miRNA to bone marrow mesenchymal stem cells (BMSC) for bone regenerative purposes, with a focus on comparing the two in terms of cell viability, transfection efficiency, and osteogenic actions. Spherical MBGN and MSN with a particle size of ~200 nm and small-sized mesopores were prepared using the sol-gel method, and then the surface was modified with polyethyleneimine for miRNA loading and delivery. The results showed miRNA can be loaded into both nanoparticles within 2 h and was released sustainedly for up to 3 days. Confocal laser scanning microscopy and flow cytometry analysis indicated a high transfection efficiency (>64%) of both nanoparticles without statistical difference. Compared with MSN, MBGN showed stronger activation of alkaline phosphatase and activation of osteocalcin genes. This translated to a greater osteogenic effect of MBGN on BMSC, with Alizarin red staining showing greater mineralization compared with the MSN group. These findings show the potential for MBGN to be used in bone tissue engineering.

13.
Front Immunol ; 13: 862866, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35898499

RESUMEN

CD4 + helper T (Th) cell subsets are critically involved in the pathogenesis of asthma. Naive Th cells differentiate into different subsets under the stimulation of different sets of cytokines, and the differentiation process is dominantly driven by lineage specific transcription factors, such as T-bet (Th1), GATA3 (Th2), RORγt (Th17) and Foxp3 (Treg). The differentiation mechanisms driven by these transcription factors are mutually exclusive, resulting in functional inhibition of these Th subsets to each other, particularly prominent between effector Th cells and Treg cells, such as Th2 versus Treg cells and Th17 versus Treg cells. Being of significance in maintaining immune homeostasis, the balance between effector Th cell response and Treg cell immunosuppression provides an immunological theoretical basis for us to understand the immunopathological mechanism and develop the therapy strategies of asthma. However, recent studies have found that certain factors involved in effector Th cells response, such as cytokines and master transcription factors (IL-12 and T-bet of Th1, IL-4 and GATA3 of Th2, IL-6 and RORγt of Th17), not only contribute to immune response of effector Th cells, but also promote the development and function of Treg cells, therefore bridging the interplay between effector Th cell immune responses and Treg cell immunosuppression. Although we have an abundant knowledge concerning the role of these cytokines and transcription factors in effector Th cell responses, our understanding on their role in Treg cell development and function is scattered thus need to be summarized. This review summarized the role of these cytokines and transcription factors involved in effector Th cell responses in the development and function of Treg cells, in the hope of providing new insights of understanding the immunopathological mechanism and seeking potential therapy strategies of asthma.


Asunto(s)
Asma , Linfocitos T Reguladores , Asma/terapia , Citocinas , Humanos , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares , Células Th17
14.
Front Pharmacol ; 13: 834009, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35273507

RESUMEN

Growing evidence suggests that long non-coding RNAs (lncRNAs) play a key role in the pathogenesis of asthma. Although some differentially expressed lncRNAs have been identified in asthmatic patients, many asthma-related lncRNAs have not been annotated. In the present study, six patients and three healthy subjects were randomly selected from 34 asthmatic patients and 17 healthy subjects. Second-generation high-throughput sequencing was performed on their peripheral blood samples. There were 1,137 differentially expressed lncRNAs in the asthma patients compared to in the healthy controls, of which 485 were upregulated and 652 were downregulated. The top 30 enriched GO and KEGG terms were identified, and the cytosolic ribosome (GO:0022626) and ribosome (hsa03010) were associated with the most differentially expressed lncRNAs. The top 10 differentially expressed lncRNAs associated with asthma were verified by an lncRNA-mRNA co-expression network and RT-qPCR. Seven of the these (NONHSAT015495.2, MSTRG.71212.2, NONHSAT163272.1, NONHSAT181891.1, NONHSAT190964.1, ENST00000564809, and NONHSAT076890.2) were down-regulated in the peripheral blood of asthmatic patients, which was consistent with the sequencing results. Three patients and three healthy subjects were randomly selected from the remaining subjects to verify these seven lncRNAs by RT-qPCR, which further confirmed the sequencing results. Public database GSE106230 was also in agreement with the FPKM (Fragments Per kilobase of exon model per Million mapped reads) trends of ENST00000564809, NONHSAT015495.2, NONHSAT181891.1, and NONHSAT190964.1. In conclusion, the present study identified seven lncRNAs that may serve as potential biological markers for asthma.

15.
Trials ; 23(1): 143, 2022 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-35164853

RESUMEN

BACKGROUND: Inhaled glucocorticoid corticosteroid (ICS), long-acting ß2-adrenoceptor agonist (LABA), and other drugs have limited therapeutic effects on COPD with significant individual differences. Traditional Chinese medicine (TCM)-modified Bushen Yiqi formula (MBYF) demonstrates advantages in COPD management in China. This study aims to evaluate the efficacy and safety of MBYF as an add-on to budesonide/formoterol in COPD patients and confirm the related genes affecting the therapeutic effect in the treatment of COPD. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, parallel-group study, eligible patients with COPD will randomly receive a 360-day placebo or MBYF as an adjuvant to budesonide/formoterol in a 1:1 ratio and be followed up with every 2 months. The primary outcomes will be the frequency, times, and severity of acute exacerbation of COPD (AECOPD), COPD assessment test (CAT) score, and pulmonary function tests (PFTs). The secondary outcomes will include the modified Medical Research Council (mMRC) dyspnoea scale, 6-min walking test (6MWT), BODE index, quantitative scores of syndromes classified in TCM, inflammation indices, and hypothalamic-pituitary-adrenaline (HPA) axis function. We will also test the genotype to determine the relationship between drugs and efficacy. All the data will be recorded in case report forms (CRFs) and analysed by SPSS V.20.0. DISCUSSION: A randomized clinical trial design to evaluate the efficacy and safety of MBYF in COPD is described. The results will provide evidence for the combination therapy of modern medicine and TCM medicine, and individual therapy for COPD. TRIAL REGISTRATION: ID:  ChiCTR1900026124 , Prospective registration.


Asunto(s)
Broncodilatadores , Enfermedad Pulmonar Obstructiva Crónica , Administración por Inhalación , Broncodilatadores/efectos adversos , Budesonida/efectos adversos , Método Doble Ciego , Quimioterapia Combinada/efectos adversos , Fumarato de Formoterol/efectos adversos , Humanos , Estudios Multicéntricos como Asunto , Estudios Prospectivos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto
16.
Phytomedicine ; 96: 153907, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35026517

RESUMEN

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a disabling/fatal disease characterized by progressive pulmonary function decline, and there are currently few drugs that can effectively reverse the decline in lung function; therefore, it is necessary to find novel drug targets. CD8+ T cells might be a new therapeutic target for alleviating lung tissue destruction and improving pulmonary function in COPD. The CXCL10/CXCR3 axis is a pivotal chemotactic axis involved in the abnormal infiltration of CD8+ T cells into the lung tissue of COPD; thus, inhibition of this axis might be a potential method to suppress CD8+ T cell-mediated lung tissue destruction in COPD. However, few drugs have been reported to target CD8+ T cells and the CXCL10/CXCR3 axis. Icaritin (ICT), one of the major components of Epimedii Folium, has been reported to have antioxidative effects in a COPD model in vitro. Whether ICT also has effects on CD8+ T cells and the CXCL10/CXCR3 axis in COPD has never been investigated. PURPOSE: This study aimed to investigate the effects of ICT on CD8+ T cell chemotaxis and the CXCL10/CXCR3 axis in interferon (IFN)-γ + cigarette smoke extract (CSE)-stimulated THP-1-derived macrophages, which simulated the pulmonary microenvironment of COPD, and then to determine the mechanisms. METHODS: The effects of ICT on the expression and secretion of CXCL9, CXCL10, and CXCL11 in THP-1-derived macrophages were measured by qRT-PCR and ELISA, and the effects of the supernatant of THP-1-derived macrophages treated with or without ICT on CD8+ T cell chemotaxis were also evaluated. Subsequently, the effects of ICT on the apoptosis and proliferation of CD8+ T cells were also assessed by EdU-488 assays and Annexin V/PI staining, respectively. Moreover, the mechanisms by which ICT inhibits the CXCL10/CXCR3 axis were investigated by RNA sequencing (RNA-seq) and KEGG pathway enrichment analysis. RESULTS: The present study showed that ICT (5 µM) significantly suppressed the expression and secretion of CXCL9, CXCL10, and CXCL11 in THP-1-derived macrophages after stimulation with IFN-γ + CSE and indirectly inhibited CD8+ T cell chemotaxis by reducing the secretion of the above chemokines. In addition, this study found that ICT had no significant effect on the proliferation of CD8+ T cells, and neither led to apoptosis. The results of the RNA-seq analysis illustrated that the transforming growth factor (TGF)-ß signaling pathway was significantly downregulated after ICT intervention, and subsequent qRT-PCR and western blotting showed that ICT could significantly downregulate the TGF-ß-Smad2 signaling pathway. CONCLUSIONS: ICT reduced CD8+ T cell chemotaxis by inhibiting the CXCL10/CXCR3 axis, and these effects might be achieved by suppressing the TGF-ß-Smad2 signaling pathway.


Asunto(s)
Linfocitos T CD8-positivos , Quimiotaxis , Quimiocina CXCL10 , Flavonoides , Receptores CXCR3 , Transducción de Señal , Fumar , Factor de Crecimiento Transformador beta
17.
Nat Rev Mater ; 6(12): 1072-1074, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34642607

RESUMEN

Silica nanoparticles have entered clinical trials for a variety of biomedical applications, including oral drug delivery, diagnostics, plasmonic resonance and photothermal ablation therapy. Preliminary results indicate the safety, efficacy and viability of silica nanoparticles under these clinical scenarios.

18.
Trends Pharmacol Sci ; 42(11): 957-972, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34593258

RESUMEN

Macromolecular therapeutics of biological origin, also known as biologics, have become one of the fastest-growing classes of drugs for management of a range of chronic and acute conditions. The majority of approved biologics are administered via the parenteral route and are thus expensive, have low patient compliance, and have high systemic toxicity. Therefore, tremendous efforts have been devoted to the development of carriers for oral delivery of biologics. This review evaluates key chemical (e.g. pH and enzymes) and physiological challenges to oral biologics delivery. We review the conventional formulation strategies and their limitations, followed by a detailed account of the progress on the use of nanocarriers used for oral biologics delivery, covering organic and inorganic nanocarriers. Lastly, we discuss limitations and opportunities presented by these emerging nanomaterials in oral biologics delivery.


Asunto(s)
Productos Biológicos , Nanopartículas , Administración Oral , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Humanos , Nanopartículas/química
19.
Mol Med Rep ; 24(5)2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34542166

RESUMEN

Cycloastragenol (CAG), a secondary metabolite from the roots of Astragalus zahlbruckneri, has been reported to exert anti­inflammatory effects in heart, skin and liver diseases. However, its role in asthma remains unclear. The present study aimed to investigate the effect of CAG on airway inflammation in an ovalbumin (OVA)­induced mouse asthma model. The current study evaluated the lung function and levels of inflammation and autophagy via measurement of airway hyperresponsiveness (AHR), lung histology examination, inflammatory cytokine measurement and western blotting, amongst other techniques. The results demonstrated that CAG attenuated OVA­induced AHR in vivo. In addition, the total number of leukocytes and eosinophils, as well as the secretion of inflammatory cytokines, including interleukin (IL)­5, IL­13 and immunoglobulin E were diminished in bronchoalveolar lavage fluid of the OVA­induced murine asthma model. Histological analysis revealed that CAG suppressed inflammatory cell infiltration and goblet cell secretion. Notably, based on molecular docking simulation, CAG was demonstrated to bind to the active site of autophagy­related gene 4­microtubule­associated proteins light chain 3 complex, which explains the reduced autophagic flux in asthma caused by CAG. The expression levels of proteins associated with autophagy pathways were inhibited following treatment with CAG. Taken together, the results of the present study suggest that CAG exerts an anti­inflammatory effect in asthma, and its role may be associated with the inhibition of autophagy in lung cells.


Asunto(s)
Antiasmáticos/farmacología , Asma/etiología , Autofagia/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Sapogeninas/farmacología , Animales , Asma/tratamiento farmacológico , Asma/metabolismo , Proteínas Relacionadas con la Autofagia/antagonistas & inhibidores , Proteínas Relacionadas con la Autofagia/química , Proteínas Relacionadas con la Autofagia/metabolismo , Biomarcadores , Biopsia , Hiperreactividad Bronquial/tratamiento farmacológico , Hiperreactividad Bronquial/etiología , Hiperreactividad Bronquial/metabolismo , Líquido del Lavado Bronquioalveolar , Citocinas/metabolismo , Manejo de la Enfermedad , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Femenino , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Inmunohistoquímica , Mediadores de Inflamación/metabolismo , Ratones , Proteínas Asociadas a Microtúbulos/antagonistas & inhibidores , Proteínas Asociadas a Microtúbulos/química , Proteínas Asociadas a Microtúbulos/metabolismo , Sapogeninas/química , Relación Estructura-Actividad
20.
Int J Pharm ; 608: 121079, 2021 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-34500058

RESUMEN

Atopic dermatitis (AD) is a repetitive inflammatory skin disorder with limited treatment options. Innovative targeted therapies are gaining significant interest and momentum towards disease control including better ways to deliver drugs topically. Tacrolimus is one such compound which is used to manage moderate to severe AD without causing atrophy which is one of the common side effects of steroids. However, Tacrolimus suffers from poor solubility and retention in the skin when used alone in hydrogel. Therefore, we have prepared Tacrolimus loaded mesoporous silica nanoparticles (TMSNs) to overcome the issues related to its solubility and effective topical delivery. Mesoporous silica nanoparticles (MSNs) were synthesized using sol gel technique and surface functionalized using amino (-NH2+) and phosphonate (-PO3-) groups. Tacrolimus was loaded into MSNs and the particles were characterized for particle size (TEM and DLS), zeta potential (DLS), solubility studies, FTIR, TGA, XRD, BET and cytotoxicity studies. Water solubility of Tacrolimus was increased by 7 folds with phosphonate functionalized MSNs compared to free Tacrolimus. Further the TMSNs were incorporated in to carbopol gel, and the gel formulation was evaluated for various gel characterization tests (pH, spreadability, viscosity), in vitro tests (drug release, permeability studies) and in vivo tests (skin irritation study and efficacy studies) using 1-Fluoro-2,4-dinitrobenzene (DNFB) induced dermatitis in Balb/c mice. Results of in vitro and in vivo study showed that TMSNs loaded gel showed significantly higher amount of Tacrolimus retained (ex vivo - rat skin) and much higher reduction in ear thickness and improved histology (in vivo - in mice). Our data collectively suggest that MSNs incorporated hydrogel as a promising new formulation strategy for topical delivery of poorly soluble drugs.


Asunto(s)
Dermatitis Atópica , Nanopartículas , Animales , Dermatitis Atópica/tratamiento farmacológico , Hidrogeles , Ratones , Porosidad , Ratas , Dióxido de Silicio , Tacrolimus
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