Supramolecular assembly and structural transformation of d10-metal complexes containing (aza-15-crown-5)dithiocarbamate.

The reaction of potassium (aza-15-crown-5)dithiocarbamate (KO4NCS2) and (Me2S)AuCl gave the dinuclear complex [Au(O4NCS2)]2, which underwent structural transformation upon heating to rearrange into the hexanuclear complex [Au(O4NCS2)]6. Under similar reaction conditions, KO4NCS2 reacted with AgNO3 or [Cu(CH3CN)4]ClO4 to give the 1-D coordination polymer [Ag(O4NCS2)]n (1) and the tetranuclear complex [Cu(O4NCS2)]4 (2), respectively. It is noted that upon heating a similar structural transformation process occurs from tetranuclear complex 2 to the octanuclear complex [Cu(O4NCS2)]8 (2'), connected by a weak Cu⋯S contact of 2.846 Å, and it has been isolated and corroborated by powder and single-crystal X-ray diffraction studies as well. Moreover, a variety of MO4NCS2 salts (M = Li+, Na+, K+ and Rb+) were used to react with AgNO3 to construct a series of coordination architectures: [LiAg(O4NCS2)2(µ-H2O)0.5]2 (3), {Na[Ag(O4NCS2)2]}n (4), {K[Ag(O4NCS2)2]}n (5) and {Rb[Ag(O4NCS2)2]}n (6). The smallest Li+ ion only coordinates with four oxygen atoms from the same azacrown ether ring and one H2O molecule, leading to a 1-D hydrogen-bonded chain with another azacrown ether ring for complex 3. The larger Na+ ion coordinates with seven oxygen atoms from two different crown ether rings, leading to a 1-D chain for complex 4. However, the largest K+ and Rb+ ions constitute a 1-D framework, except that each metal ion coordinates with eight oxygen atoms from two different crown ether rings, featuring a 1-D helical chain for complexes 5 and 6. Hence, the different sizes of alkaline metal ions exert a dramatic effect on the structural motifs of complexes 3-6. Remarkably, the dithiocarbamate moieties adopt µ2-bridging ([Au(O4NCS2)]2 and [Au(O4NCS2)]6), µ3- and µ4-bridging (1-2) and chelate forms (3-6) in the structural backbones.

Development of Irinotecan Liposome Armed with Dual-Target Anti-Epidermal Growth Factor Receptor and Anti-Fibroblast Activation Protein-Specific Antibody for Pancreatic Cancer Treatment.

Pancreatic cancer is one of the most common causes of death in Taiwan. Previous studies have shown that more than 90% of pancreatic cancer cells presented epidermal growth factor receptor (EGFR) cell marker, and this marker is thought to be important as it is related to activation of cancer cell proliferation, angiogenesis, and cancer progression. Moreover, tumor-associated fibroblasts were involved in tumor proliferation and progression. In this study, we fabricated an anti-EGFR and anti-fibroblast activation protein bispecific antibody-targeted liposomal irinotecan (BS-LipoIRI), which could specifically bind to pancreatic cancer cells and tumor-associated fibroblasts. The drug encapsulation efficiency of BS-LipoIRI was 80.95%, and the drug loading was 8.41%. We proved that both pancreatic cancer cells and fibroblasts could be targeted by BS-LipoIRI, which showed better cellular uptake efficacy compared to LipoIRI. Furthermore, an in vivo mouse tumor test indicated that BS-LipoIRI could inhibit pancreatic cancer growth up to 46.2% compared to phosphate-buffered saline control, suggesting that BS-LipoIRI could be useful in clinical cancer treatment.

Reduction of breast tumor drug resistance by 2,3,5,4'-tetrahydroxystilbene for exhibition synergic chemotherapeutic effect.

Chemotherapy drugs have limited efficacy in breast cancer due to multidrug resistance generated by cancer cells against anticancer drugs. In this study, we developed a novel derivative, 2, 3, 5, 4'-tetrahydroxystilbene (TG1) by modifying 2, 3, 5, 4'-tetrahydroxystilbene-2-O-beta-D-glucoside (THSG). In-vivo zebrafish embryo tests revealed that TG1 showed low toxicity. The equitoxic combination of DOX or DTX with TG1 in MCF-7/Adr reduced the IC50 of DOX or DTX, and the combination index (CI) showed strong synergistic effects in the 1:3 molar ratio of DTX: TG1 and 1:5 molar ratio of DOX: TG1. Moreover, fluorescence images confirmed the cellular uptake of DOX when combined with TG1 in MCF-7/Adr. Western blotting analysis indicated downregulation of p-glycoprotein (P-gp) after MCF-7/Adr treated with TG1. In conclusion, the combined therapy of DTX or DOX and TG1 increases drug efficacy via suppressing the p-glycoprotein efflux pump. These results suggest that TG1 may have potential use for breast cancer patients, especially those with multidrug resistance.

Midline and Mediolateral Episiotomy: Risk Assessment Based on Clinical Anatomy.

Episiotomy is the surgical incision of the vaginal orifice and perineum to ease the passage of an infant's head while crowning during vaginal delivery. Although episiotomy remains one of the most frequently performed surgeries around the world, short- and long-term complications from the procedure are not uncommon. We performed midline and mediolateral episiotomies with the aim of correlating commonly diagnosed postepisiotomy complications with risk of injury to perineal neuromuscular and erectile structures. We performed 61 incisions on 47 female cadavers and dissected around the incision site. Dissections revealed that midline incisions did not bisect any major neuromuscular structures, although they did increase the risk of direct and indirect injury to the subcutaneous portion of the external anal sphincter. Mediolateral incisions posed greater risk of iatrogenic injury to ipsilateral nerve, muscle, erectile, and gland tissues. Clinician discretion is advised when weighing the potential risks to maternal perineal anatomy during vaginal delivery when episiotomy is indicated. If episiotomy is warranted, an understanding of perineal anatomy may benefit diagnosis of postsurgical complications.

Solvent-Induced Luminescence and Structural Transformation of a Dinuclear Gold(I) (Aza-18-crown-6)dithiocarbamate Compound.

The reaction of AuCl(SMe2) with equimolar NaO5NCS2 [O5NCS2 = (aza-18-crown-6)dithiocarbamate] in CH3CN gave [Au2(O5NCS2)2]·2CH3CN (2·2CH3CN), where six other 2·solvates (solvates = 2DMF, 2DMSO, 2THF, 2acetone, 1.5toluene, and 1.5anisole) can be successfully isolated from different crystal-growing processes (i.e., ether diffusion, layer method, or evaporation in air) by dissolving the dry powder samples of 2·2CH3CN in the respective solvents, and their crystal structures are all determined by X-ray diffraction as well. It is noted that there are different intermolecular Au(I)···Au(I) contacts in combination with various luminescences for 2·solvates and indeed there is a close relationship between intermolecular Au(I)···Au(I) contacts [i.e., 2.8254(7)-2.9420(5) Å] and luminescence energies (i.e., 554-604 nm), including three examples of 2·2CH3CN, 2·0.5m-xylene, and 2·tert-butylbenzene·H2O reported in our previous work. In 2·solvates, the toluene and tert-butylbenzene solvates have the shortest [2.8254(7)-2.8289(7) Å] and longest [2.9420(5) Å] intermolecular Au(I)···Au(I) contacts, respectively, and consequently they show the respective lowest (604 nm) and highest (554 nm) luminescence energies. Indeed, 2·solvates exhibit different types of time-dependent luminescence upon solvate loss in air. Furthermore, B3LYP/LanL2DZ calculation results can help to clarify the relationship between intermolecular Au(I)···Au(I) contacts and luminescence energies for 2·solvates.

Decellularized Lymph Node Scaffolding as a Carrier for Dendritic Cells to Induce Anti-Tumor Immunity.

In recent decades, the decellularized extracellular matrix (ECM) has shown potential as a promising scaffold for tissue regeneration. In this study, an organic acid decellularized lymph node (dLN) was developed as a carrier for dendritic cells (DCs) to induce antitumor immunity. The dLNs were prepared by formic acid, acetic acid, or citric acid treatment. The results showed highly efficient removal of cell debris from the lymph node and great preservation of ECM architecture and biomolecules. In addition, bone marrow dendritic cells (BMDCs) grown preferably inside the dLN displayed the maturation markers CD80, CD86, and major histocompatibility complex (MHC)-II, and they produced high levels of interleukin (IL)-1ß, IL-6, and IL-12 cytokines when stimulated with ovalbumin (OVA) and CpG oligodeoxynucleotides (CPG-ODN). In an animal model, the BMDC-dLN completely rejected the E.G7-OVA tumor. Furthermore, the splenocytes from BMDC-dLN-immunized mice produced more interferon gamma, IL-4, IL-6, and IL-2, and they had a higher proliferation rate than other groups when re-stimulated with OVA. Hence, BMDC-dLN could be a promising DC-based scaffold for in vivo delivery to induce potent antitumor immunity.

Exercise and resveratrol increase fracture resistance in the 3xTg-AD mouse model of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) and osteoporosis are progressive diseases that affect the elderly population. Both conditions are associated with fracture risk that is greater than twice that of the healthy population. Resveratrol and exercise are two treatments that have been linked with attenuation of age-related diseases, including the risk of bone fractures. In this study, we test the hypothesis that these treatments improve fracture resistance in a mouse model representative of the AD condition. METHODS: Three-month-old male 3xTg-AD mice were treated for 4 months with resveratrol or exercise or both combined, and compared with wild type mice. Exercise training was performed on a treadmill at 15 m/min for 45 min/day, 5 days/week. Resveratrol was given at 4 g/kg diet in the form of pellets. Three-point bending, cross-sectional geometric, and fluorescence analyses were conducted on tibias and compared by treatment group. RESULTS: Tibias of 3xTg mice exhibited signs of diminished bone quality and fracture under less force than age-matched wild type mice (P < 0.05). Treatment with both resveratrol and exercise improved indicators of fracture resistance and bone quality in AD mice to levels comparable to that of wild type mice (P < 0.05). CONCLUSIONS: The 3xTg mouse model of AD is at elevated risk for limb bone fracture compared to wild type controls. Treatment with resveratrol, exercise, or both in combination improves fracture resistance and cross-sectional geometric indicators of bone strength.

Leptin-deficient mice have altered three-dimensional growth plate histomorphometry.

BACKGROUND: Leptin is an adipokine that regulates energy homeostasis and is also needed for normal bone growth and maintenance. Mutation in the lep gene, which characterizes the ob/ob mouse model, results in the development of obesity and type 2 diabetes mellitus, as well as reduced limb bone length and increased fracture risk. However, the relationship between limb bone length and growth plate cartilage structure in obese diabetic adolescents is incompletely understood. Here, we tested the hypothesis that leptin deficiency affects the microstructure of growth plate cartilage in juvenile ob/ob mice. METHODS: Tibial growth plate cartilage structure was compared between lean and obese, leptin-deficient (ob/ob) female mice aged 10 weeks. We used confocal laser scanning microscopy to assess 3D histological differences in Z stacks of growth plate cartilage at 0.2 µm intervals, 80-100 µm in depth. Histomorphometric comparisons were made between juvenile lean and ob/ob mice. RESULTS: We found obese mice have significantly reduced tibial length and growth plate height in comparison with lean mice (P < 0.05). Obese mice also have fewer chondrocyte columns in growth plate cartilage with reduced chondrocyte cell volumes relative to lean mice (P < 0.05). CONCLUSIONS: These data help explicate the relationship between growth plate cartilage structure and bone health in obese diabetic juvenile mice. Our findings suggest obesity and diabetes may adversely affect growth plate cartilage structure.

Development of Decellularized Cornea by Organic Acid Treatment for Corneal Regeneration.

IMPACT STATEMENT: This study successfully developed decellularized corneal scaffolds that were prepared by organic acid, which safely exist in animal tissues and plants. The results showed the highly efficient removal of cell debris from porcine corneas, and excellent preservation of optical properties, extracellular matrix (ECM) architecture, and biomolecules. In addition, decellularized corneal scaffolds revealed excellent biocompatibility and recellularization potential in vitro. In an animal model, the transplanted corneas were completely epithelialized, clear, showed no signs of immune response, and effectively supported stromal keratocytes growth. Hence, this could be a promising scaffold material for corneal tissue engineering applications.

Otitis Media and Nasopharyngeal Colonization in ccl3-/- Mice.

We previously found CC chemokine ligand 3 (CCL3) to be a potent effector of inflammation during otitis media (OM): exogenous CCL3 rescues the OM phenotype of tumor necrosis factor-deficient mice and the function of macrophages deficient in several innate immune molecules. To further delineate the role of CCL3 in OM, we evaluated middle ear (ME) responses of ccl3-/-mice to nontypeable Haemophilus influenzae (NTHi). CCL chemokine gene expression was evaluated in wild-type (WT) mice during the complete course of acute OM. OM was induced in ccl3-/- and WT mice, and infection and inflammation were monitored for 21 days. Phagocytosis and killing of NTHi by macrophages were evaluated by an in vitro assay. The nasopharyngeal bacterial load was assessed in naive animals of both strains. Many CCL genes showed increased expression levels during acute OM, with CCL3 being the most upregulated, at levels 600-fold higher than the baseline. ccl3-/- deletion compromised ME bacterial clearance and prolonged mucosal hyperplasia. ME recruitment of leukocytes was delayed but persisted far longer than in WT mice. These events were linked to a decrease in the macrophage capacity for NTHi phagocytosis and increased nasopharyngeal bacterial loads in ccl3-/- mice. The generalized impairment in inflammatory cell recruitment was associated with compensatory changes in the expression profiles of CCL2, CCL7, and CCL12. CCL3 plays a significant role in the clearance of infection and resolution of inflammation and contributes to mucosal host defense of the nasopharyngeal niche, a reservoir for ME and upper respiratory infections. Therapies based on CCL3 could prove useful in treating or preventing persistent disease.

Galactosylated liposome as a dendritic cell-targeted mucosal vaccine for inducing protective anti-tumor immunity.

Mucosal surfaces contain specialized dendritic cells (DCs) that are able to recognize foreign pathogens and mount protective immunity. We previously demonstrated that intranasal administration of targeted galactosylated liposomes can elicit mucosal and systemic antibody responses. In the present study, we assessed whether galactosylated liposomes could act as an effective DC-targeted mucosal vaccine that would be capable of inducing systemic anti-tumor immunity as well as antibody responses. We show that targeted galactosylated liposomes effectively facilitated antigen uptake by DCs beyond that mediated by unmodified liposomes both in vitro and in vivo. Targeted galactosylated liposomes induced higher levels of pro-inflammatory cytokines than unmodified liposomes in vitro. C57BL/6 mice thrice immunized intranasally with ovalbumin (OVA)-encapsulated galactosylated liposomes produced high levels of OVA-specific IgG antibodies in their serum. Spleen cells from mice receiving galactosylated liposomes were restimulated with OVA and showed significantly augmented levels of IFN-γ, IL-4, IL-5 and IL-6. In addition, intranasal administration of OVA-encapsulated beta-galactosylated liposomes resulted in complete protection against EG7 tumor challenge in C57BL/6 mice. Taken together, these results indicate that nasal administration of a galactosylated liposome vaccine mediates the development of an effective immunity against tumors and might be useful for further clinical anti-tumoral applications.

Phenol soluble modulin (PSM) variants of community-associated methicillin-resistant Staphylococcus aureus (MRSA) captured using mass spectrometry-based molecular networking.

Molecular genetic analysis indicates that the problematic human bacterial pathogen methicillin-resistant Staphylococcus aureus possesses more than 2000 open reading frames in its genome. This number of potential gene products, coupled with intrinsic mechanisms of posttranslational modification, endows methicillin-resistant Staphylococcus aureus with a highly complex biochemical repertoire. Recent proteomic and metabolomic advances have provided methodologies to better understand and characterize the biosynthetic factors released by microbial organisms. Here, the emerging tool of mass spectrometry-based molecular networking was used to visualize and map the repertoire of biosynthetic factors produced by a community-associated methicillin-resistant Staphylococcus aureus strain representative of the epidemic USA300 clone. In particular, the study focused on elucidating the complexity of the recently discovered phenol soluble modulin family of peptides when placed under various antibiotic treatment stresses. Novel PSM truncated variant peptides were captured, and the type of variants that were clustered by the molecular networks platform changed in response to the different antibiotic treatment conditions. After discovery, a group of the peptides were selected for functional analysis in vitro. The peptides displayed bioactive properties including the ability to induce proinflammatory responses in human THP-1 monocytes. Additionally, the tested peptides did not display antimicrobial activity as previously reported for other phenol soluble modulin truncated variants. Our findings reveal that the PSM family of peptides are quite structurally diverse, and suggest a single phenol soluble modulin parent peptide can functionally spawn differential bioactivities in response to various external stimuli.

Bioremediation potential of soil contaminated with highly substituted polychlorinated dibenzo-p-dioxins and dibenzofurans: microcosm study and microbial community analysis.

Highly chlorinated dibenzo-p-dioxins/dibenzofurans (DD/Fs) are main hazardous dioxins, and ubiquitously distributed in the environment. To study the feasibility of bioremediation for remedying contamination of highly chlorinated dioxins, closed microcosms were constructed with soil from a chronological site under oxygen-stimulated conditions. The results showed that high levels of near-fully and fully chlorinated DD/Fs, particularly octachlorodibenzofuran were effectually reduced without accumulation of less substituted congeners. The clone library analysis of PCR-amplified 16S rRNA gene from the octachlorodibenzofuran-degrading consortia showed that 98.3% of the detected sequences were affiliated with Proteobacteria. The obtained strains with putative aromatic dioxygenase genes and abilities to repetitively grow in octachlorodibenzofuran-containing agars were closely related to members within Actinobacteria, Firmicutes, and Proteobacteria. Among them, certain Rhodococcus, Micrococcus, Mesorhizobium and Bacillus isolates could degrade octachlorodibenzofuran with efficiencies of 26-43% within 21 days. Hierarchical oligonucleotide primer extension analysis further showed that Micrococcus, Rhizobium, Pseudoxanthomonas, and Brevudimonas populations increased largely when high concentrations of octachlorodibenzofuran were reduced. Overall, our results suggest that a distinctive microbial composition and population dynamic could be required for the enhanced degradation of highly chlorinated DD/Fs in the batch microcosm and highlight a potential of bioremediation technologies in remedying polychlorinated dioxins in the polluted sites.

An energy-harvesting scheme employing CuGaSe2 quantum dot-modified ZnO buffer layers for drastic conversion efficiency enhancement in inorganic-organic hybrid solar cells.

We demonstrated a promising route to enhance the performance of inverted organic photovoltaic (OPV) devices by the incorporation of CuGaSe2 (CGS) quantum dots (QDs) into the ZnO buffer layer of P3HT:PCBM-based devices. The modification of QDs provides better band alignment between the organic/cathode interface, improves ZnO crystal quality, and increases photon absorption, leading to more effective carrier transport/collection. By employing this energy-harvesting scheme, short-circuit current density, open-circuit voltage, and fill factor of the OPV device after CGS QD modification are improved by 9.43%, 7.02% and 6.31%, respectively, giving rise to a 23.8% enhancement in the power conversion efficiency.

Application of galactose-modified liposomes as a potent antigen presenting cell targeted carrier for intranasal immunization.

The mucosal immune system produces secretory IgA (sIgA) as the first line of defense against invasion by foreign pathogens. Our aim was to develop a galactose-modified liposome as a targeted carrier which can be specifically recognized by macrophage, one of the most important antigen presenting cells. First, galactose was covalently conjugated with 1,2-didodecanoyl-sn-glycero-3-phosphoethanolamine (DLPE) to give a targeted ligand, a galactosyl lipid. The galactosyl lipid was then incorporated into a liposomal bilayer to form a galactosylated liposome carrier. Further, the ovalbumin (OVA) was encapsulated into the galactosylated liposome carriers and mice were intranasally immunized. Confocal laser scanning microscopy and flow cytometry analysis showed that the targeted galactosylated liposome carrier had a higher uptake rate than unmodified liposomes. The targeted galactosylated liposome induced higher levels of tumor necrosis factor-α and interleukin-6 production than unmodified liposomes (P<0.05). Furthermore, 6-week-old BALB/c female mice immunized with the OVA-encapsulated targeted galactosylated liposome had significantly higher OVA-specific s-IgA levels in the nasal and lung wash fluid (P<0.05). In addition, the targeted galactosylated liposome simultaneously augmented the serum IgG antibody response. In summary, the OVA-encapsulated targeted galactosylated liposome induced significantly higher mucosal IgA and systemic IgG antibody titers and is a potential antigen delivery carrier for further clinical applications.

Expression of CDK 4, Connexin 32, and PCNA in N-diethylnitrosamine-Induced Lesions of Rat Liver

Cellular altered foci (CAF), hyperplastic nodules (HN) including regenerating and adenomatous nodules, and hepatocellular carcinomas (HCC) were induced in Sprague-Dawley rat liver by prolonged administration of N-diethylnitrosamine (DEN, 200 ppm). Immunohistochemical expression of connexin 32 (Cx 32), cyclin-dependent kinase 4 (CDK 4), and proliferating cell nuclear antigen (PCNA) was assessed for the evaluation of preneoplastic potential of CAF. Regardless the duration of DEN administration, basophilic cell foci were the most frequently observed lesion in both CAF and cellular expanding hyperplastic nodules. Eosinophilic cell foci, however, were concomitantly increased with adenomatous nodules in later experimental groups. Cx 32 showed perimembranous spot-like expression. Its number was 7.25 2.10 per cell in normal hepatocytes. CAF and adenomatous nodules showed markedly decreased Cx 32 spots. Moreover, its reduction was more prominent in HCC. PCNA-labelled hepatocytes were scattered in the most CAF, showing no significant difference between each CAF. PCNA labelling index (LI) in adenomatous nodule and HCC was markedly increased. CDK 4 was localized in the cytoplasm and/or nucleus of hepatocytes. Eosinophilic cell foci revealed more nuclear expression of CDK 4 than other types of CAF, of which expression incidence was comparable to that of adenomatous nodule. Nuclear CDK 4 expression in HN and HCC was increased, although significant difference between regenerating nodule and adenomatous nodule was not seen. In conclusion, the incidence of CDK 4 was concomitantly increased with PCNA LI, however, reciprocally decreased with Cx 32 in accordance with the advance of DEN-induced HCC in rat. Phenotypically altered foci manifested as CAF are early valuable preneoplastic marker lesion for evaluation. In addition, basophilic cell foci can be considered a discernible marker of cellular expansion within nodules. However, eosinophilic cell foci might be an indeterminate marker for the advance of DEN-induced HCC in rat.

Clinical evaluation of therapeutic trial for unresectable hepatocellular carcinoma

No abstract available.