Heterogeneous distributions in clinical events preceding anticoagulant treatment nonpersistence in patients with venous thromboembolism stratified by active cancer: A nationwide cohort study.

BACKGROUND: Nonpersistence in anticoagulation therapy is common and associated with undesirable clinical outcomes in patients with venous thromboembolism (VTE). METHODS: We investigated preceding clinical events of treatment nonpersistence (e.g., switching, discontinuing, or restarting) in VTE patients with and without active cancer using Korean claims database. RESULTS: Clinically significant events including thromboembolic events, hepatic function change and surgery preceded treatment nonpersistence, but heterogeneous distributions of clinical events were observed in the presence of active cancer. Patients with active cancer had a low rate of clinical events preceding treatment nonpersistence, and new active cancer diagnosis in the nonactive cancer group was most common before the switch to parenteral anticoagulants from warfarin or non-vitamin K antagonist oral anticoagulants (NOACs). CONCLUSION: These findings suggest that clinically significant events can precede treatment nonpersistence and largely paralleled current guidelines for patients with VTE, whereas heterogeneous distributions of clinical events were observed in the presence of active cancer.

Axon guidance gene-targeted siRNA delivery system improves neural stem cell transplantation therapy after spinal cord injury.

BACKGROUND: Neural stem cells (NSCs) derived from the embryonic spinal cord are excellent candidates for the cellular regeneration of lost neural cells after spinal cord injury (SCI). Semaphorin 3 A (Sema3A) is well known as being implicated in the major axon guidance of the growth cone as a repulsive function during the development of the central nervous system, yet its function in NSC transplantation therapy for SCI has not been investigated. Here, we report for the first time that embryonic spinal cord-derived NSCs significantly express Sema3A in the SCI environment, potentially facilitating inhibition of cell proliferation after transplantation. METHODS: siRNA-Sema3A was conjugated with poly-l-lysin-coated gold nanoparticles (AuNPs) through a charge interaction process. NSCs were isolated from embryonic spinal cords of rats. Then, the cells were embedded into a dual-degradable hydrogel with the siRNA- Sema3A loaded-AuNPs and transplanted after complete SCI in rats. RESULTS: The knockdown of Sema3A by delivering siRNA nanoparticles via dual-degradable hydrogels led to a significant increase in cell survival and neuronal differentiation of the transplanted NSCs after SCI. Of note, the knockdown of Sema3A increased the synaptic connectivity of transplanted NSC in the injured spinal cord. Moreover, extracellular matrix molecule and functional recovery were significantly improved in Sema3A-inhibited rats compared to those in rats with only NSCs transplanted. CONCLUSIONS: These findings demonstrate the important role of Sema3A in NSC transplantation therapy, which may be considered as a future cell transplantation therapy for SCI cases.

Intramuscular administration of recombinant Newcastle disease virus expressing SARS-CoV-2 spike protein protects hACE-2 TG mice against SARS-CoV-2 infection.

Coronavirus disease 2019 (Covid-19) caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) became a pandemic, causing significant burden on public health worldwide. Although the timely development and production of mRNA and adenoviral vector vaccines against SARS-CoV-2 have been successful, issues still exist in vaccine platforms for wide use and production. With the potential for proliferative capability and heat stability, the Newcastle disease virus (NDV)-vectored vaccine is a highly economical and conceivable candidate for treating emerging diseases. In this study, a recombinant NDV-vectored vaccine expressing the spike (S) protein of SARS-CoV-2, rK148/beta-S, was developed and evaluated for its efficacy against SARS-CoV-2 in K18-hACE-2 transgenic mice. Intramuscular vaccination with low dose (106.0 EID50) conferred a survival rate of 76 % after lethal challenge of a SARS-CoV-2 beta (B.1.351) variant. When administered with a high dose (107.0 EID50), vaccinated mice exhibited 100 % survival rate and reduced lung viral load against both beta and delta variants (B.1.617.2). Together with the protective immunity, rK148/beta-S is an accessible and cost-effective SARS-CoV-2 vaccine.

BAP1 as a guardian of genome stability: implications in human cancer.

BAP1 is a ubiquitin C-terminal hydrolase domain-containing deubiquitinase with a wide array of biological activities. Studies in which advanced sequencing technologies were used have uncovered a link between BAP1 and human cancer. Somatic and germline mutations of the BAP1 gene have been identified in multiple human cancers, with a particularly high frequency in mesothelioma, uveal melanoma and clear cell renal cell carcinoma. BAP1 cancer syndrome highlights that all carriers of inherited BAP1-inactivating mutations develop at least one and often multiple cancers with high penetrance during their lifetime. These findings, together with substantial evidence indicating the involvement of BAP1 in many cancer-related biological activities, strongly suggest that BAP1 functions as a tumor suppressor. Nonetheless, the mechanisms that account for the tumor suppressor function of BAP1 have only begun to be elucidated. Recently, the roles of BAP1 in genome stability and apoptosis have drawn considerable attention, and they are compelling candidates for key mechanistic factors. In this review, we focus on genome stability and summarize the details of the cellular and molecular functions of BAP1 in DNA repair and replication, which are crucial for genome integrity, and discuss the implications for BAP1-associated cancer and relevant therapeutic strategies. We also highlight some unresolved issues and potential future research directions.

Targeting BAP1 with small compound inhibitor for colon cancer treatment.

BRCA1-associated protein-1 (BAP1) is a ubiquitin C-terminal hydrolase domain-containing deubiquitinase. The gene encoding BAP1 is mutated in various human cancers, including mesothelioma, uveal melanoma and renal cell carcinoma. BAP1 plays roles in many cancer-related cellular functions, including cell proliferation, cell death, and nuclear processes crucial for genome stability, such as DNA repair and replication. While these findings suggest that BAP1 functions as a tumor suppressor, recent data also suggest that BAP1 might play tumor-promoting roles in certain cancers, such as breast cancer and hematopoietic malignancies. Here, we show that BAP1 is upregulated in colon cancer cells and tissues and that BAP1 depletion reduces colon cancer cell proliferation and tumor growth. BAP1 contributes to colon cancer cell proliferation by accelerating DNA replication and suppressing replication stress and concomitant apoptosis. A recently identified BAP1 inhibitor, TG2-179-1, which seems to covalently bind to the active site of BAP1, exhibits potent cytotoxic activity against colon cancer cells, with half-maximal inhibitory concentrations of less than 10 µM, and inhibits colon tumor growth. TG2-179-1 exerts cytotoxic activity by targeting BAP1, leading to defective replication and increased apoptosis. This work therefore shows that BAP1 acts oncogenically in colon cancer and is a potential therapeutic target for this cancer. Our work also suggests that TG2-179-1 can be developed as a potential therapeutic agent for colon cancer.

Berberine Induces Mitophagy through Adenosine Monophosphate-Activated Protein Kinase and Ameliorates Mitochondrial Dysfunction in PINK1 Knockout Mouse Embryonic Fibroblasts.

Mitophagy stimulation has been shown to have a therapeutic effect on various neurodegenerative diseases. However, nontoxic mitophagy inducers are still very limited. In this study, we found that the natural alkaloid berberine exhibited mitophagy stimulation activity in various human cells. Berberine did not interfere with mitochondrial function, unlike the well-known mitophagy inducer carbonyl cyanide m-chlorophenyl hydrazone (CCCP), and subsequently induced mitochondrial biogenesis. Berberine treatment induced the activation of adenosine monophosphate-activated protein kinase (AMPK), and the AMPK inhibitor compound C abolished berberine-induced mitophagy, suggesting that AMPK activation is essential for berberine-induced mitophagy. Notably, berberine treatment reversed mitochondrial dysfunction in PINK1 knockout mouse embryonic fibroblasts. Our results suggest that berberine is a mitophagy-specific inducer and can be used as a therapeutic treatment for neurodegenerative diseases, including Parkinson's disease, and that natural alkaloids are potential sources of mitophagy inducers.

Transplantation of neuron-inducing grafts embedding positively charged gold nanoparticles for the treatment of spinal cord injury.

In this study, we aimed to investigate the recovery after traumatic spinal cord injury (SCI) by inducing cellular differentiation of transplanted neural stem cells (NSCs) into neurons. We dissociated NSCs from the spinal cords of Fisher 344 rat embryos. An injectable gel crosslinked with glycol chitosan and oxidized hyaluronate was used as a vehicle for NSC transplantation. The gel graft containing the NSC and positively charged gold nanoparticles (pGNP) was implanted into spinal cord lesions in Sprague-Dawley rats (NSC-pGNP gel group). Cellular differentiation of grafted NSCs into neurons (stained with ß-tubulin III [also called Tuj1]) was significantly increased in the NSC-pGNP gel group (***p < 0.001) compared to those of two control groups (NSC and NSC gel groups) in the SCI conditions. The NSC-pGNP gel group showed the lowest differentiation into astrocytes (stained with glial fibrillary acidic protein). Regeneration of damaged axons (stained with biotinylated dextran amines) within the lesion was two-fold higher in the NSC-pGNP gel group than that in the NSC gel group. The highest locomotor scores were also found in the NSC-pGNP gel group. These outcomes suggest that neuron-inducing pGNP gel graft embedding embryonic spinal cord-derived NSCs can be a useful type of stem cell therapy after SCI.

BAP1 promotes the repair of UV-induced DNA damage via PARP1-mediated recruitment to damage sites and control of activity and stability.

BRCA1-associated protein-1 (BAP1) is a ubiquitin C-terminal hydrolase domain-containing deubiquitinase with tumor suppressor activity. The gene encoding BAP1 is mutated in various human cancers, with particularly high frequency in kidney and skin cancers, and BAP1 is involved in many cancer-related cellular functions, such as DNA repair and genome stability. Although BAP1 stimulates DNA double-strand break repair, whether it functions in nucleotide excision repair (NER) is unknown. Here, we show that BAP1 promotes the repair of ultraviolet (UV)-induced DNA damage via its deubiquitination activity in various cell types, including primary melanocytes. Poly(ADP-ribose) polymerase 1 (PARP1) interacts with and recruits BAP1 to damage sites, with BAP1 recruitment peaking after the DDB2 and XPC damage sensors. BAP1 recruitment also requires histone H2A monoubiquitinated at Lys119, which accumulates at damage sites. PARP1 transiently poly(ADP-ribosyl)ates (PARylates) BAP1 at multiple sites after UV damage and stimulates the deubiquitination activity of BAP1 both intrinsically and via PARylation. PARP1 also promotes BAP1 stability via crosstalk between PARylation and ubiquitination. Many PARylation sites in BAP1 are mutated in various human cancers, among which the glutamic acid (Glu) residue at position 31, with particularly frequent mutation in kidney cancer, plays a critical role in BAP1 stabilization and promotes UV-induced DNA damage repair. Glu31 also participates in reducing the viability of kidney cancer cells. This study therefore reveals that BAP1 functions in the NER pathway and that PARP1 plays a role as a novel factor that regulates BAP1 enzymatic activity, protein stability, and recruitment to damage sites. This activity of BAP1 in NER, along with its cancer cell viability-reducing activity, may account for its tumor suppressor function.

Genetic Characterization and Pathogenicity Analysis of Recently Isolated Fowl Adenovirus 8b in Korea.

A Korean field strain of fowl adenovirus (FAdV) 8b was isolated from chickens showing high mortality. Isolated FAdV-8b strains with the hexon and fiber genes were genetically analyzed. The Korean FAdV-8b (K194/19) strain isolated in 2019 showed higher sequence identity with the FAdV-8b strain isolated in China but lower sequence identity with the Korean FAdV-8b (K187/08) strain isolated in 2008. The K194/19 strain formed a distinct subcluster within the FAdV-8b cluster in a phylogenetic tree based on hexon and fiber genes. FAdV can infect day-old chicks through vertical transmission, and so blood samples were obtained from 54-, 60-, and 63-wk-old parent chickens. FAdV-specific antibody levels were investigated with ELISA and virus neutralization (VN) tests with the K194/19 and K187/08 strains as antigens. In VN tests, all sera neutralized the K187/08 strain. However, the K194/19 strain was neutralized by sera collected from 60- and 63-wk-old chickens but not sera obtained from 54-wk-old chickens, indicating natural infection. Finally, to determine the pathogenicity of the K194/19 strain, 1-day-old and 4-wk-old specific-pathogen-free birds were infected with the K194/19 and K187/08 strains. No significant difference in pathogenicity was observed between the two strains. Although the K194/19 strain showed similar pathogenicity with the K187/08 strain, differences in nucleotide and amino acid sequences of the hexon and fiber genes may determine the evasion ability of the K187/08 neutralizing antibody, indicating the need for development of a novel FAdV vaccine.

Nota de investigación­Caracterización genética y análisis de patogenicidad de un adenovirus del pollo 8b aislado recientemente en Corea. Se aisló una cepa de campo coreana de adenovirus del pollo (FAdV) 8b de aves que mostraban una alta mortalidad. Se analizaron genéticamente cepas de FAdV-8b aisladas mediante los genes de hexón y de la fibra. La cepa coreana FAdV-8b (K194/19) aislada en 2019 mostró una mayor identidad de secuencia con la cepa FAdV-8b aislada en China, pero una menor identidad de secuencia con la cepa coreana FAdV-8b (K187/08) aislada en 2008. La cepa K194/19 formó un subgrupo distinto dentro del grupo de adenovirus del pollo 8b en un árbol filogenético basado en los genes de las fibras y hexones. El FAdV puede infectar a pollitos de un día a través de la transmisión vertical, por lo que se obtuvieron muestras de sangre de pollos reproductores de 54, 60 y 63 semanas de edad. Los niveles de anticuerpos específicos de FAdV se investigaron con ELISA y pruebas de neutralización de virus (VN) con las cepas K194/19 y K187/08 como antígenos. En las pruebas de neutralización, todos los sueros neutralizaron a la cepa K187/08. Sin embargo, la cepa K194/19 fue neutralizada por sueros recolectados de pollos de 60 y 63 semanas de edad, pero no por los sueros obtenidos de pollos de 54 semanas de edad, lo que indica una infección natural. Finalmente, para determinar la patogenicidad de la cepa K194/19, se infectaron aves libres de patógenos específicos de un día y cuatro semanas de edad con las cepas K194/19 y K187/08. No se observaron diferencias significativas en la patogenicidad entre las dos cepas. Aunque la cepa K194/19 mostró una patogenicidad similar con la cepa K187/08, las diferencias en las secuencias de nucleótidos y aminoácidos de los genes del hexón y de la fibra pueden determinar la capacidad para evadir los anticuerpos neutralizantes K187/08, lo que indica la necesidad de desarrollar una nueva vacuna contra adenovirus del pollo.

Transplantation of tauroursodeoxycholic acid-inducing M2-phenotype macrophages promotes an anti-neuroinflammatory effect and functional recovery after spinal cord injury in rats.

OBJECTIVES: In this study, we study the transplantation of tauroursodeoxycholic acid (TUDCA)-induced M2-phenotype (M2) macrophages and their ability to promote anti-neuroinflammatory effects and functional recovery in a spinal cord injury (SCI) model. METHODS: To this end, compared to the granulocyte-macrophage colony-stimulating factor (GM-CSF), we evaluated whether TUDCA effectively differentiates bone marrow-derived macrophages (BMDMs) into M2 macrophages. RESULTS: The M2 expression markers in the TUDCA-treated BMDM group were increased more than those in the GM-CSF-treated BMDM group. After the SCI and transplantation steps, pro-inflammatory cytokine levels and the mitogen-activated protein kinase (MAPK) pathway were significantly decreased in the TUDCA-induced M2 group more than they were in the GM-CSF-induced M1 group and in the TUDCA group. Moreover, the TUDCA-induced M2 group showed significantly enhanced tissue volumes and improved motor functions compared to the GM-CSF-induced M1 group and the TUDCA group. In addition, biotinylated dextran amine (BDA)-labelled corticospinal tract (CST) axons and neuronal nuclei marker (NeuN) levels were increased in the TUDCA-induced M2 group more than those in the GM-CSF-induced M1 group and the TUDCA group. CONCLUSIONS: This study demonstrates that the transplantation of TUDCA-induced M2 macrophages promotes an anti-neuroinflammatory effect and motor function recovery in SCI. Therefore, we suggest that the transplantation of TUDCA-induced M2 macrophages represents a possible alternative cell therapy for SCI.

The Bromodomain Inhibitor PFI-3 Sensitizes Cancer Cells to DNA Damage by Targeting SWI/SNF.

Many chemotherapeutic drugs produce double-strand breaks (DSB) on cancer cell DNA, thereby inducing cell death. However, the DNA damage response (DDR) enables cancer cells to overcome DNA damage and escape cell death, often leading to therapeutic resistance and unsuccessful outcomes. It is therefore important to develop inhibitors that target DDR proteins to render cancer cells hypersensitive to DNA damage. Here, we investigated the applicability of PFI-3, a recently developed bromodomain inhibitor specifically targeting the SWI/SNF chromatin remodeler that functions to promote DSB repair, in cancer treatment. We verified that PFI-3 effectively blocks chromatin binding of its target bromodomains and dissociates the corresponding SWI/SNF proteins from chromatin. We then found that, while having little toxicity as a single agent, PFI-3 synergistically sensitizes several human cancer cell lines to DNA damage induced by chemotherapeutic drugs such as doxorubicin. This PFI-3 activity occurs only for the cancer cells that require SWI/SNF for DNA repair. Our mechanism studies show that PFI-3 exerts the DNA damage-sensitizing effect by directly blocking SWI/SNF's chromatin binding, which leads to defects in DSB repair and aberrations in damage checkpoints, eventually resulting in increase of cell death primarily via necrosis and senescence. This work therefore demonstrates the activity of PFI-3 to sensitize cancer cells to DNA damage and its mechanism of action via SWI/SNF targeting, providing an experimental rationale for developing PFI-3 as a sensitizing agent in cancer chemotherapy. IMPLICATIONS: This study, revealing the activity of PFI-3 to sensitize cancer cells to chemotherapeutic drugs, provides an experimental rationale for developing this bromodomain inhibitor as a sensitizing agent in cancer chemotherapy.

Cytotoxic activity of bromodomain inhibitor NVS-CECR2-1 on human cancer cells.

Bromodomain (BRD), a protein module that recognizes acetylated lysine residues on histones and other proteins, has recently emerged as a promising therapeutic target for human diseases such as cancer. While most of the studies have been focused on inhibitors against BRDs of the bromo- and extra-terminal domain (BET) family proteins, non-BET family BRD inhibitors remain largely unexplored. Here, we investigated a potential anticancer activity of the recently developed non-BET family BRD inhibitor NVS-CECR2-1 that targets the cat eye syndrome chromosome region, candidate 2 (CECR2). We show that NVS-CECR2-1 inhibits chromatin binding of CECR2 BRD and displaces CECR2 from chromatin within cells. NVS-CECR2-1 exhibits cytotoxic activity against various human cancer cells, killing SW48 colon cancer cells in particular with a submicromolar half maximum inhibition value mainly by inducing apoptosis. The sensitivity of the cancer cells to NVS-CECR2-1 is reduced by CECR2 depletion, suggesting that NVS-CECR2-1 exerts its activity by targeting CECR2. Interestingly, our data show that NVS-CECR2-1 also kills cancer cells by CECR2-independent mechanism. This study reports for the first time the cancer cell cytotoxic activity for NVS-CECR2-1 and provides a possibility of this BRD inhibitor to be developed as an anticancer therapeutic agent.

Injectable Hydrogel Containing Tauroursodeoxycholic Acid for Anti-neuroinflammatory Therapy After Spinal Cord Injury in Rats.

We investigate the anti-inflammatory effects of injectable hydrogel containing tauroursodeoxycholic acid (TUDCA) in a spinal cord injury (SCI) model. To this end, TUDCA-hydrogel (TC gel) is created by immersing the synthesized hydrogel in a TUDCA solution for 1 h. A mechanical SCI was imposed on rats, after which we injected the TC gel. After the SCI and injections, motor functions and lesions were significantly improved in the TC gel group compared with those in the saline group. The TC gel significantly decreased pro-inflammatory cytokine levels compared with the saline; TUDCA and glycol chitosan-oxidized hyaluronate were mixed at a ratio of 9:1 (CHA) gel independently. In addition, the TC gel significantly suppressed the phosphorylation of extracellular signal-regulated kinase (p-ERK) and c-Jun N-terminal kinase (p-JNK) in the mitogen-activated protein kinase (MAPK) pathway compared with the saline, TUDCA, and CHA gel independently. It also decreased tumor necrosis factor-α (TNF-α) and glial fibrillary acidic protein (GFAP), inflammatory marker, at the injured sites more than those in the saline, TUDCA, and CHA gel groups. In conclusion, the results of this study demonstrate the neuroinflammatory inhibition effects of TC gel in SCI and suggest that TC gel can be an alternative drug system for SCI cases.

p53 regulates mitochondrial dynamics by inhibiting Drp1 translocation into mitochondria during cellular senescence.

Cellular senescence acts as an important barrier to tumorigenesis by eliminating precancerous cells. Previous studies have shown an essential role of the tumor suppressor p53 in cellular senescence, but how p53 induces cellular senescence is not fully understood. We found that p53 promoted the formation of highly interconnected and elongated mitochondria prior to the onset of cellular senescence. The inhibition of mitochondrial elongation upon p53 expression suppressed cellular senescence, suggesting that mitochondrial elongation is required for the induction of p53-dependent senescence. p53-induced mitochondrial elongation resulted in mitochondrial dysfunction and subsequent increases in intracellular reactive oxygen species (ROS) levels, an important mediator of cellular senescence. Mechanistically, the inhibitory phosphorylation of Drp1 Ser637 increased upon p53 expression, suppressing the translocation of Drp1 into mitochondria. The transcriptional function of p53 was crucial for controlling the inhibitory phosphorylation of Drp1, whereas p21 was nonessential. Protein kinase A (PKA) activity was responsible for p53-mediated Drp1 Ser637 phosphorylation and mitochondrial dysfunction. Taken together, these results suggest that p53 regulates mitochondrial dynamics through the PKA-Drp1 pathway to induce cellular senescence.

Gadolinium-Encapsulated Graphene Carbon Nanotheranostics for Imaging-Guided Photodynamic Therapy.

Photosensitizers (PS) are an essential component of photodynamic therapy (PDT). Conventional PSs are often porphyrin derivatives, which are associated with high hydrophobicity, low quantum yield in aqueous solutions, and suboptimal tumor-to-normal-tissue (T/N) selectivity. There have been extensive efforts to load PSs into nanoparticle carriers to improve pharmacokinetics. The approach, however, is often limited by PS self-quenching, pre-mature release, and nanoparticle accumulation in the reticuloendothelial system organs. Herein, a novel, nanoparticle-based PS made of gadolinium-encapsulated graphene carbon nanoparticles (Gd@GCNs), which feature a high 1 O2 quantum yield, is reported. Meanwhile, Gd@GCNs afford strong fluorescence and high T1 relaxivity (16.0 × 10-3 m-1 s-1 , 7 T), making them an intrinsically dual-modal imaging probe. Having a size of approximately 5 nm, Gd@GCNs can accumulate in tumors through the enhanced permeability and retention effect. The unbound Gd@GCNs cause little toxicity because Gd is safely encapsulated within an inert carbon shell and because the particles are efficiently excreted from the host through renal clearance. Studies with rodent tumor models demonstrate the potential of the Gd@GCNs to mediate image-guided PDT for cancer treatment. Overall, the present study shows that Gd@GCNs possess unique physical, pharmaceutical, and toxicological properties and are an all-in-one nanotheranostic tool with substantial clinical translation potential.

Inhibitory effect of Patrinia scabiosifolia Link on the development of atopic dermatitis-like lesions in human keratinocytes and NC/Nga mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Atopic dermatitis (AD) is a chronic pruritic and inflammatory disease occurring in skin. Patrinia scabiosifolia Link (PS), a member of the Patrinia genus (Caprifoliaceae family), has traditionally been used in folk medicines to treat various inflammatory diseases such as acute appendicitis, ulcerative colitis, and pelvic inflammation in Korea and other parts of East Asia. AIM OF THE STUDY: This study investigated the anti-inflammatory effects of PS on AD in vitro and in vivo. MATERIALS AND METHODS: Whole PS plants were dried, powdered, and then underwent extraction with DMSO. Both ELISA and western blotting were performed to evaluate cytokine concentration and the expression and activation of filaggrin and signaling proteins. Five-week-old female NC/Nga mice were used as an AD-like mouse model by treating them with 2,4-dinitrochlorobenzene (DNCB). RESULTS: In human keratinocytic HaCaT cells, PS extract inhibited the production of IL-8, and TARC, which had been increased by TNF-α and IFN-γ. The TNF-α and IFN-γ suppressed filaggrin expression was associated with phosphorylation of JNK1 and JNK2, and NF-κB translocation. PS recovered the inhibition of filaggrin expression induced by TNF-α and IFN-γ by blocking the activation of JNK1/2, and NF-κB by the IFN-γ and TNF-α treatment. The in vivo experiment results showed that, compared to DNCB treatment PS administration reduced thickening of the epidermis and infiltration of inflammatory cells into the dermis. Moreover, the decrease of filaggrin expression due to DNCB treatment was recovered by PS administration. The serum IgE level was decreased by PS treatment. Additionally, secretions of IL-4, IL-5, IL-13, and eotaxin in splenocytes were lower in the PS-treated group than in the DNCB group. CONCLUSION: PS may attenuate the development of AD-like lesions by increasing filaggrin expression and lowering IgE and inflammatory cytokine levels. These results indicate the potential for development of a PS-based drug treatment for AD.

Gd and Eu Co-Doped Nanoscale Metal-Organic Framework as a T1-T2 Dual-Modal Contrast Agent for Magnetic Resonance Imaging.

Recently, a growing interest has been seen in the development of T1-T2 dual-mode probes that can simultaneously enhance contrast on T1- and T2-weighted images. A common strategy is to integrate T1 and T2 components in a decoupled manner into a nanoscale particle. This approach, however, often requires a multi-step synthesis and delicate nanoengineering, which may potentially affect the production and wide application of the probes. We herein report the facile synthesis of a 50-nm nanoscale metal-organic framework (NMOF) comprising gadolinium (Gd3+) and europium (Eu3+) as metallic nodes. These nanoparticles can be prepared in large quantities and can be easily coated with a layer of silica. The yielded Eu,Gd-NMOF@SiO2 nanoparticles are less toxic, highly fluorescent, and afford high longitudinal (38 mM-1s-1) and transversal (222 mM-1s-1) relaxivities on a 7 T magnet. The nanoparticles were conjugated with c(RGDyK), a tumor-targeting peptide sequence, which has a high binding affinity toward integrin αvß3. Eu,Gd-NMOF@SiO2 nanoparticles, when intratumorally or intravenously injected, induce simultaneous signal enhancement and signal attenuation on T1-and T2-weighted images, respectively. These results suggest great potential of the NMOFs as a novel T1-T2 dual-mode contrast agent.