•Indocyanine green is a photosensitizer approved for clinical use.•Anionic indocyanine green is unstable and hardly permeates through skin.•Topical photodynamic therapy is noninvasive strategy for ...melanoma treatment.•Chitosan-coating of liposomes can protect indocyanine green from degradation.•Chitosan-coated liposomes enhances skin permeation of indocyanine green.
Indocyanine green (ICG) has been used clinically and noticed as a promising candidate for the topical melanoma photodynamic therapy (PDT). Despite its high potentials in topical PDT, the use of ICG has been hampered by the instability in aqueous solution. In the present study, chitosan-coated liposomes were adopted as a formulation strategy which could stabilize and enhance skin permeation of ICG. Chitosan-coating was verified by the significantly increased liposomal size and reversed zeta potential from negative to positive value by positive chitosan coating. Chitosan-coating liposomes protected ICG from degradation while uncoated liposomes did not. Moreover, they significantly increased cellular uptake and photocytotoxicity of ICG in B16-F10 melanoma cells in a chitosan-dependent manner. The skin permeation of ICG was also drastically improved by chitosan-coated liposomes. These findings emphasize the promising potential of ICG-loaded chitosan-coated liposomes for topical PDT of melanoma.
The blood-brain barrier (BBB) maintains homeostasis of the brain environment by tightly regulating the entry of substances from systemic circulation. A breach in the BBB results in increased ...permeability to potentially toxic substances and is an important contributor to amplification of ischemic brain damage. The precise molecular pathways that result in impairment of BBB integrity remain to be elucidated. Autophagy is a degradation pathway that clears damaged or unnecessary proteins from cells. However, excessive autophagy can lead to cellular dysfunction and death under pathological conditions.
In this study, we investigated whether autophagy is involved in BBB disruption in ischemia, using in vitro cells and in vivo rat models. We used brain endothelial bEnd.3 cells and oxygen glucose deprivation (OGD) to simulate ischemia in culture, along with a rat ischemic stroke model to evaluate the role of autophagy in BBB disruption during cerebral ischemia.
OGD 18 h induced cellular dysfunction, and increased permeability with degradation of occludin and activation of autophagy pathways in brain endothelial cells. Immunostaining revealed that occludin degradation is co-localized with ischemic autophagosomes. OGD-induced occludin degradation and permeability changes were significantly decreased by inhibition of autophagy using 3-methyladenine (3-MA). Enhanced autophagic activity and loss of occludin were also observed in brain capillaries isolated from rats with middle cerebral artery occlusion (MCAO). Intravenous administration of 3-MA inhibited these molecular changes in brain capillaries, and recovered the increased permeability as determined using Evans blue.
Our findings provide evidence that autophagy plays an important role in ischemia-induced occludin degradation and loss of BBB integrity.
Abstract
Precise control of morphology and optical response of 3-dimensional chiral nanoparticles remain as a significant challenge. This work demonstrates chiral gold nanoparticle synthesis using ...single-stranded oligonucleotide as a chiral shape modifier. The homo-oligonucleotide composed of Adenine nucleobase specifically show a distinct chirality development with a dissymmetric factor up to g ~ 0.04 at visible wavelength, whereas other nucleobases show no development of chirality. The synthesized nanoparticle shows a counter-clockwise rotation of generated chiral arms with approximately 200 nm edge length. The molecular dynamics and density functional theory simulations reveal that Adenine shows the highest enantioselective interaction with Au(321)
R/S
facet in terms of binding orientation and affinity. This is attributed to the formation of sequence-specific intra-strand hydrogen bonding between nucleobases. We also found that different sequence programming of Adenine-and Cytosine-based oligomers result in chiral gold nanoparticles’ morphological and optical change. These results extend our understanding of the biomolecule-directed synthesis of chiral gold nanoparticles to sequence programmable deoxyribonucleic acid and provides a foundation for programmable synthesis of chiral gold nanoparticles.
Various non-invasive administrations have recently emerged as an alternative to conventional needle injections. A transdermal drug delivery system (TDDS) represents the most attractive method among ...these because of its low rejection rate, excellent ease of administration, and superb convenience and persistence among patients. TDDS could be applicable in not only pharmaceuticals but also in the skin care industry, including cosmetics. Because this method mainly involves local administration, it can prevent local buildup in drug concentration and nonspecific delivery to tissues not targeted by the drug. However, the physicochemical properties of the skin translate to multiple obstacles and restrictions in transdermal delivery, with numerous investigations conducted to overcome these bottlenecks. In this review, we describe the different types of available TDDS methods, along with a critical discussion of the specific advantages and disadvantages, characterization methods, and potential of each method. Progress in research on these alternative methods has established the high efficiency inherent to TDDS, which is expected to find applications in a wide range of fields.
The engulfment adaptor phosphotyrosine‐binding domain containing 1 (GULP1) is an adaptor protein involved in the engulfment of apoptotic cells via phagocytosis. Gulp1 was first found to promote the ...phagocytosis of apoptotic cells by macrophages, and its role in various tissues, including neurons and ovaries, has been well studied. However, the expression and function of GULP1 in bone tissue are poorly understood. Consequently, to determine whether GULP1 plays a role in the regulation of bone remodeling in vitro and in vivo, we generated Gulp1 knockout (KO) mice. Gulp1 was expressed in bone tissue, mainly in osteoblasts, while its expression is very low in osteoclasts. Microcomputed tomography and histomorphometry analysis in 8‐week‐old male Gulp1 KO mice revealed a high bone mass in comparison with male wild‐type (WT) mice. This was a result of decreased osteoclast differentiation and function in vivo and in vitro as confirmed by a reduced actin ring and microtubule formation in osteoclasts. Gas chromatography‐mass spectrometry analysis further showed that both 17β‐estradiol (E2) and 2‐hydroxyestradiol levels, and the E2/testosterone metabolic ratio, reflecting aromatase activity, were also higher in the bone marrow of male Gulp1 KO mice than in male WT mice. Consistent with mass spectrometry analysis, aromatase enzymatic activity was significantly higher in the bone marrow of male Gulp1 KO mice. Altogether, our results suggest that GULP1 deficiency decreases the differentiation and function of osteoclasts themselves and increases sex steroid hormone‐mediated inhibition of osteoclast differentiation and function, rather than affecting osteoblasts, resulting in a high bone mass in male mice. To the best of our knowledge, this is the first study to explore the direct and indirect roles of GULP1 in bone remodeling, providing new insights into its regulation.
Targeted protein degradation allows targeting undruggable proteins for therapeutic applications as well as eliminating proteins of interest for research purposes. While several degraders that harness ...the proteasome or the lysosome have been developed, a technology that simultaneously degrades targets and accelerates cellular autophagic flux is still missing. In this study, we develop a general chemical tool and platform technology termed AUTOphagy-TArgeting Chimera (AUTOTAC), which employs bifunctional molecules composed of target-binding ligands linked to autophagy-targeting ligands. AUTOTACs bind the ZZ domain of the otherwise dormant autophagy receptor p62/Sequestosome-1/SQSTM1, which is activated into oligomeric bodies in complex with targets for their sequestration and degradation. We use AUTOTACs to degrade various oncoproteins and degradation-resistant aggregates in neurodegeneration at nanomolar DC
values in vitro and in vivo. AUTOTAC provides a platform for selective proteolysis in basic research and drug development.
The reduction of carbon dioxide (CO2) into chemical feedstock is drawing increasing attention as a prominent method of recycling atmospheric CO2. Although many studies have been devoted in designing ...an efficient catalyst for CO2 conversion with noble metals, low selectivity and high energy input still remain major hurdles. One possible solution is to use the combination of an earth‐abundant electrocatalyst with a photoelectrode powered by solar energy. Herein, for the first time, a p‐type silicon nanowire with nitrogen‐doped graphene quantum sheets (N‐GQSs) as heterogeneous electrocatalyst for selective CO production is demonstrated. The photoreduction of CO2 into CO is achieved at a potential of −1.53 V versus Ag/Ag+, providing 0.15 mA cm−2 of current density, which is 130 mV higher than that of a p‐type Si nanowire decorated with well‐known Cu catalyst. The faradaic efficiency for CO is 95%, demonstrating significantly improved selectivity compared with that of bare planar Si. The density functional theory (DFT) calculations are performed, which suggest that pyridinic N acts as the active site and band alignment can be achieved for N‐GQSs larger than 3 nm. The demonstrated high efficiency of the catalytic system provides new insights for the development of nonprecious, environmentally benign CO2 utilization.
Highly selective CO2 to CO photoconversion catalyzed by N‐doped graphene quantum sheets (N‐GQSs) on a p‐type Si nanowire is demonstrated. The photocatalytic system produces CO with the chemical selectivity of more than 95%, which is comparable with that of the noble metals such as Au and Re. The developed system provides a new means for utilizing CO2 as a usable chemical feedstock.
Many studies have focused on global hypomethylation or hypermethylation of tumor suppressor genes, but less is known about the impact of promoter hypomethylation of oncogenes. We previously showed ...that promoter methylation may gradually increase or decrease during the transition from gastric mucosa (GM) to intestinal metaplasia (IM) to gastric cancer (GC). In our study, we focused on regional CpG hypomethylation of the promoter‐proximal DNA of the transcription factor ONECUT2 (OC2) in IM and GC cells. We validated the hypomethylation of promoter‐proximal DNA of OC2 in 160 primary GCs, in which methylation level correlated negatively with OC2 mRNA level. IM and GC cells stained positively for OC2, whereas GM cells did not. Stable transfection of OC2 in GC cells promoted colony formation, cell migration, invasion and proliferation. Moreover, OC2 knockdown with a short hairpin RNA suppressed tumorigenesis in nude mice. In addition, chromatin immunoprecipitation coupled with DNA sequencing and RNA‐seq analyses revealed that OC2 triggered ACSL5, which is strongly expressed in IM of the stomach but not in GM, indicating that OC2 and ACSL5 are early‐stage biomarkers for GC. We also observed a high correlation between the levels of OC2 and ACSL5 mRNAs in the GENT database These results suggest that epigenetic alteration of OC2 upregulates its expression, which then activates ACSL5; thus, OC2 is induced in IM by epigenetic alteration and triggers ACSL5 expression, and thus OC2 and ACSL5 may cooperatively promote intestinal differentiation and GC progression.
What's new?
DNA hypomethylation can promote cancer development through activation of genes with oncogenic potential. Here, the authors found that CpGs in the promoter‐proximal DNA of ONECUT2 were hypomethylated in intestinal metaplasia and gastric cancers, and that hypomethylation was associated with ONECUT2 upregulation. Functional analysis demonstrated that ONECUT2 has oncogenic potential and could activate ACSL5, which is also expressed in intestinal metaplasia, suggesting that ONECUT2 and ACSL5 may cooperate to promote intestinal differentiation or development of gastric cancer. Taken together, the findings suggest that ONECUT2 and its downstream target ACSL5 could be used to develop early detection biomarkers and prevent gastric carcinogenesis.
Coxsackievirus B3 (CVB3) is an important human pathogen associated with the development of acute pancreatitis, myocarditis, and type 1 diabetes. Currently, no vaccines or antiviral therapeutics are ...approved for the prevention and treatment of CVB3 infection. We found that Saururus chinensis Baill extract showed critical antiviral activity against CVB3 infection in vitro. Further, manassantin B inhibited replication of CVB3 and suppressed CVB3 VP1 protein expression in vitro. Additionally, oral administration of manassantin B in mice attenuated CVB3 infection-associated symptoms by reducing systemic production of inflammatory cytokines and chemokines including TNF-α, IL-6, IFN-γ, CCL2, and CXCL-1. We found that the antiviral activity of manassantin B is associated with increased levels of mitochondrial ROS (mROS). Inhibition of mROS generation attenuated the antiviral activity of manassantin B in vitro. Interestingly, we found that manassantin B also induced cytosolic release of mitochondrial DNA based on cytochrome C oxidase DNA levels. We further confirmed that STING and IRF-3 expression and STING and TBK-1 phosphorylation were increased by manassantin B treatment in CVB3-infected cells. Collectively, these results suggest that manassantin B exerts antiviral activity against CVB3 through activation of the STING/TKB-1/IRF3 antiviral pathway and increased production of mROS.
A class of imprintable, bendable, and shape‐conformable polymer electrolyte with excellent electrochemical performance in a lithium battery system is reported. The material consists of a UV‐cured ...polymer matrix, high‐boiling point liquid electrolyte, and Al2O3 nanoparticles, formulated for use in lithium‐ion batteries with 3D‐structured electrodes or flexible characteristics. The unique structural design and well‐tuned rheological characteristics of the UV‐curable electrolyte mixture, in combination with direct UV‐assisted nanoimprint lithography, allow the successful fabrication of polymer electrolytes in geometries not accessible with conventional materials.
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