Photoactivatable aggregation-induced emission luminogens based on photodehydrogenation reactions for biomedical applications.

The development of photoactivatable aggregation-induced emission (AIE) probes is one of the hotspots for bioimaging and imaging-guided precise disease therapy due to the distinct advantages of high spatiotemporal resolution, precise spatiotemporal controllability, and noninvasiveness of light. To design and develop novel photoactivatable AIE probes, functional groups based on photodehydrogenation reaction mechanisms are combined with the AIE-active skeleton. Here, the recent progress in biomedical applications of photoactivatable AIE probes based on photocyclodehydrogenation and photo-oxidative dehydrogenation reactions are summarized briefly. Moreover, the outlook for photoactivatable AIE probes is discussed to aim at promoting innovative research in biomedical applications.

Translational Selenium Nanoparticles to Attenuate Allergic Dermatitis through Nrf2-Keap1-Driven Activation of Selenoproteins.

Easy recurrence and strong treatment side effects significantly limit the clinical treatment of allergic dermatitis. The human trace element selenium (Se) plays essential roles in redox regulation through incorporation into selenoproteins in the form of 21st necessary amino acid selenocysteine, to participates in the pathogenesis and intervention of chronic inflammatory diseases. Therefore, based on the safe and elemental properties of Se, we construct a facile-synthesis strategy for antiallergic selenium nanoparticles (LET-SeNPs), and scale up the production by employing a spray drying method with lactose (Lac-LET-SeNPs) or maltodextrin (Mal-LET-SeNPs) as encapsulation agents realizing larger scale production and a longer storage time. As expected, these as-prepared LET-SeNPs could effectively activate the Nrf2-Keap1 signaling pathway to enhance the expression of antioxidative selenoprotein at mRNA and protein levels, then inhibit mast cell activation to achieve efficient antiallergic activity. Interestingly, LET-SeNPs undergo metabolism to seleno-amino acids to promote biosynthesis of selenoproteins, which could suppress ROS-induced cyclooxygenase-2 (COX-2) and MAPKs activation to suppress the release of histamine and inflammatory cytokines. Allergic mouse and Macaca fascicularis models further confirm that LET-SeNPs could increase the Se content and selenoprotein expression in the skin, decrease mast cells activation and inflammatory cells infiltration, and finally exhibit the high therapeutic effects on allergic dermatitis. Taken together, this study not only constructs facile large-scale synthesis of translational Se nanomedicine to break through the bottleneck problem of nanomaterials but also sheds light on its application in the intervention and treatment of allergies.

Targeting MEX3A attenuates metastasis of breast cancer via ß-catenin signaling pathway inhibition.

Metastasis is the major cause of mortality in patients with breast cancer. Understanding the metastatic mechanism to guide clinical diagnoses and the treatment of breast cancer remains a challenge. We found that the expression of Mex-3 RNA binding family member A (MEX3A) was upregulated significantly and related to tumor grade in breast cancer. The results of in vitro and in vivo studies showed that knockdown of MEX3A inhibited the metastasis and impaired the stemness of breast cancer cells. Furthermore, activation of the ß-catenin signaling pathway was discovered as a molecular intermediate of MEX3A-mediated regulation. We also found that ectopic expression of ß-catenin restored the migration ability, invasion ability, and CD44+/CD24- percentage of MDA-MB-231 and BT549 cells when MEX3A was depleted. In addition, we revealed that MEX3A positively regulated the expression of ß-catenin by downregulating Dickkopf WNT signaling pathway inhibitor 1 (DKK1) expression. Therefore, a previously undiscovered role of MEX3A comprising a critical contribution to promoting metastasis and maintaining the stemness of breast cancer via the Wnt/ß-catenin pathway was demonstrated in the present study.

Designing Dihydrofolate Reductase Inhibitors as X-ray Radiosensitizers to Reverse Radioresistance of Cervical Cancer.

X-ray radiotherapy has been widely used in the treatment of cervical cancer, a common gynecologic malignant tumor. However, the therapeutic efficacy tends to be indistinctive. One major reason for this is amplification of the dihydrofolate reductase (DHFR) gene, which causes an increase in DHFR activity and attenuation of the treatment effect. To solve this problem, we synthesized a series of DHFR inhibitors derived from methotrexate (MTX) analogues as radiotherapy sensitizers. Activity screening revealed that compound 2a exerted the best inhibitory effect toward DHFR activity. In combination with X-ray radiotherapy (4 Gy), 2a showed much more prominent antiproliferative activity on cervical cancer cells than 2a or X-rays alone and revealed higher selectivity and radiosensitization than MTX. In vitro experiments showed that 2a + X-rays significantly induced cell apoptosis, as revealed by the increase in the Sub-G1 population and activation of caspase 3, 8, and 9. The in vivo antitumor effect demonstrated that in the presence of X-rays, 2a effectively suppressed tumor growth and did not cause obvious side effects. In conclusion, as a DHFR inhibitor, 2a successfully reversed the radioresistance problem induced by radiotherapy and greatly promoted the therapeutic effect. This is a promising candidate for tumor treatment that deserves further research and development. This study clearly demonstrates that DHFR inhibitors could be developed as promising radiosensitizers in the treatment of cervical cancer and that further research to improve their activity and potential in future clinical use is deserved.

Airway management in inhalation injury: a case series.

Inhalation injury is a serious consequence of a fire or an explosion, with potential airway compromise and respiratory complications. We present a case series of five patients with inhalational burns who presented to Singapore General Hospital and discuss our approach to their early management, including early evaluation and planning for the upper and lower airway, coexisting cutaneous burns, and monitoring their ICU (intensive care unit) severity of illness, sepsis and acute respiratory distress syndrome. All five patients suffered various grades of inhalation injury. The patients were initially assessed by nasolaryngoscopy, and three patients were prophylactically intubated before being sent to the emergency operating theatre for definitive airway and burns management with fibreoptic bronchoscopy. All patients were successfully extubated and discharged stable. Various complications can arise as a result of an inhalation injury. Based on our cases and literature review, we propose a standardised workflow for patients with inhalation injury.

Selenium-containing ruthenium complex synergizes with natural killer cells to enhance immunotherapy against prostate cancer via activating TRAIL/FasL signaling.

Natural killer (NK) cells-based therapy has been used widely for cancer treatment in clinic trails. However, the immunotherapeutic efficacy of this method has been greatly hindered by tumor evasion and diminished activities of NK cells. In the present study, a selenium (Se)-bearing ruthenium (Ru) complex (RuSe) was designed that could synergistically potentiate NK cell-mediated killing against prostate cancer cells. As expected, pretreatment of cancer cells with subtoxic doses of RuSe effectively augmented the lysis potency of NK cells, with up to 2.46-fold enhancement than NK cells alone, against PC3 cells. More importantly, low concentrations of RuSe could augment the tumor destroying potency of NK cells derived from 10 clinical patients, with the enhancement range from 0.78- to 11.9-fold against PC3 cells and 0.67- to 3.8-fold against LNCAP cells. Mechanistic studies revealed that the sensitizing effect of RuSe primarily depended on TRAIL/TRAIL-R and Fas/FasL-mediated signaling. Furthermore, the increased expression level of these ligands highly relied on ROS overproduction-triggered DNA damage and the downstream ATM and ATR pathways. Furthermore, RuSe potently activated and synergized with NK cells to restrain tumor growth in vivo without causing toxic side effects on major organs. Taken together, the current study not only provides a strategy for application of metal complexes in chemo-immunotherapy but also sheds light on the potential roles and mechanisms of action on such Se-containing drugs as efficient immune-sensitizing agents for NK cell-based immunotherapy.

Potentiation of in Vivo Anticancer Efficacy of Selenium Nanoparticles by Mushroom Polysaccharides Surface Decoration.

Selenium nanoparticles (SeNPs) are recently emerging as promising anticancer agents because of their high bioavailability, low toxicity and remarkable anticancer activities. However, the effects of surface physicochemical properties on the biological actions remain elusive. Herein we decorated SeNPs with various water-soluble polysaccharides extracted from various mushrooms, to compare physical characteristics and anticancer profile of these SeNPs. The results showed that the prepared spherical SeNPs displayed particle sizes at 91-102 nm, and kept stable in aqueous solution for up to 13 weeks. However, different decoration altered the tumor selectivity of the SeNPs, while gastric adenocarcinoma AGS cells showed relative highest sensitivity. Moreover, PTR-SeNPs demonstrated potent in vivo antitumor, by inducing caspases- and mitochondria-mediated apoptosis, but showed no obvious toxicity to nomal organs. Taken together, this study offers insights into how surface decoration can tune the cancer selectivity of SeNPs and provides a basis for engineering particles with increased anticancer efficacy.

Cancer-targeted design of bioresponsive prodrug with enhanced cellular uptake to achieve precise cancer therapy.

Chemical drug design based on the biochemical characteristics of cancer cells has become an important strategy for discovery of novel anticancer drugs to enhance the cancer targeting effects and biocompatibility, and decrease toxic side effects. Camptothecin (CPT) demonstrated strong anticancer activity in clinical trials but also notorious adverse effects. In this study, we presented a smart targeted delivery system (Biotin-ss-CPT) that consists of cancer-targeted moiety (biotin), a cleavable disulfide linker (S-S bond) and the active drug CPT. Biotin-ss-CPT was found to exhibit potent effects on the migration of cancer cells and induced apoptosis by induction of ROS-mediated mitochondrial dysfunction and perturbation of GSH/GPXs system, as well as activation of caspases. In vivo tumor suppression investigation including toxicity evaluation and pathology analysis, accompanied by MR images showed that Biotin-ss-CPT can be recognized specifically and selectively and taken up preferentially by cancers cells, followed by localization and accumulation effectively in tumor site, then released CPT by biological response to achieve high therapeutic effect and remarkably reduced the side effects that free CPT caused, such as liver damage, renal injury, and weight loss to realize precise cancer therapy. Taken together, our results suggest that biotinylation and bioresponsive functionalization of anticancer drugs could be a good way for the discovery of next-generation cancer therapeutics.

Rational Design of Cancer-Targeted Selenadiazole Derivative as Efficient Radiosensitizer for Precise Cancer Therapy.

Chemical drug design based on the biochemical characteristics of cancer cells has become an important strategy for discovery of targeted therapies for personalized cancer medicine. Herein, cancer targeting RGD peptide has been covalently conjugated to selenadiazole derivative (RGD-SeD) to improve its cancer selectivity. The RGD decoration significantly enhances the anticancer efficacy of RGD-SeD in αVß3 integrin-overexpressing HepG2 liver cancer cells but not in normal liver cells. Cellular uptake assay and fluorescent imaging confirmed the selectivity of RGD-SeD to integrin-overexpressing cancer cells. RGD-SeD strongly sensitizes HepG2 cells to clinically used X-ray radiotherapy through ROS overproduction, which triggers DNA damage-mediated apoptosis and G2/M cell cycle arrest. This X-ray-responsive DNA damage activates p53 signaling pathways by phosphorylation of ATM/ATR and γ-H2A.X. Furthermore, in a HepG2 nude mice xenograft model, the combined treatment of RGD-SeD and X-ray demonstrates potent in vivo antitumor efficacy via induction of apoptotic cell death but shows no toxicity on the functions of major organs. In summary, this study provides a strategy to design a selenium-based cancer targeting radiosensitizer for precise cancer therapy.

Selenadiazole derivatives antagonize hyperglycemia-induced drug resistance in breast cancer cells by activation of AMPK pathways.

Hyperglycemia is an important factor for chemoresistance of breast cancer patients with diabetes. In the present study, a novel selenadiazole derivative has been evaluated and found to be able to antagonize the doxorubicin (DOX) resistance of MCF-7 cells under simulated diabetes conditions. Hyperglycemia promotes the proliferation, invasion and migration of MCF-7 cells through activation of ERK and AKT pathways, which could be inhibited by the synthetic selenadiazole derivative. The antitumor effects of the selenadiazole derivative were attributed to its ability to activate AMPK pathways. Furthermore, the high lipophilicity (log P = 1.9) of the synthetic selenadiazole derivative facilitated its uptake by cancer cells and subsequently potentiated the cellular uptake of DOX, leading to a strong enhancment of the antiproliferative activity of DOX on MCF-7 cells by induction of apoptosis. The apoptosis was initiated by the ROS overproduction induced by the cooperation of the selenadiazole derivative and DOX. The excessive ROS then caused damage to DNA, which upregulated the expression of proapoptosis Bcl-2 family proteins and led to fragmentation of mitochondria, which finally caused apoptosis of the cancer cells. Taken together, this study provides a rational strategy for using selenadiazole derivatives to overcome hyperglycemia-induced drug resistance in breast cancer by activation of AMPK-mediated pathways.

Blocking EZH2 methylation transferase activity by GSK126 decreases stem cell-like myeloma cells.

EZH2 is a critical epigenetic regulator that is deregulated in various types of cancers including multiple myeloma (MM). In the present study, we hypothesized that targeting EZH2 might induce apoptosis in myeloma cells including stem cell-like cells (CSCs). We investigated the effect of EZH2 inhibition on MM cells using a potent inhibitor (GSK126). The results showed that GSK126 effectively abrogated the methylated histone 3 (H3K27me3) level in MM.1S and LP1 cells, and inhibited the number of live cells and colony formation in soft agar of six MM cell lines. GSK126 induced massive apoptosis in MM.1S, LP1 and RPMI8226 cells. Progressive release of mitochondrial cytochrome c and AIF into the cytosol was detected in GSK126-treated MM cells. GSK126 treatment elicited caspase-3-dependent MCL-1 cleavage with accumulation of proapoptotic truncated MCL-1. These results suggested that GSK126 triggers the intrinsic mitochondrial apoptosis pathway. Enhanced apoptosis was observed in the combination of GSK126 with bortezomib. Using ALDH and side population (SP) assays to characterize CSCs, we found that GSK126 eliminated the stem-like myeloma cells by blocking the Wnt/ß-catenin pathway. The in vivo anti-tumor effect of GSK126 was confirmed by using RPMI8226 cells in a xenograft mouse model. In conclusion, our findings suggest that EZH2 inactivation by GSK126 is effective in killing MM cells and CSCs as a single agent or in combination with bortezomib. Clinical trial of GSK126 in patients with MM may be warranted.

Complete mitochondrial genome of Takydromus sexlineatus (Squamata, Lacertidae).

The complete sequence mitochondrial genome of Takydromus sexlineatus was determined using long PCR and conserved primers walking approaches. The genome was 18,943 bp in length and contained 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and 1 control region (CR). The gene composition and order of T. sexlineatus were similar to most other squamate reptiles. All protein-coding genes begin with ATG as initiation codon except COI using GTG. Seven genes (ATP8. ND4L. ND5. Cytb. ND1. COI and ND6) ended with TAA, TAG, AGGA and AGA stop codon, the remaining 6 genes had incomplete stop codons T/TA. The overall base composition of the genome in descending order was 31.48% A, 24.67% C, 30.79% T and 13.05% G, with a slight A + T bias of 62.27%. CR is located between the tRNA-Pro and tRNA-Phe genes and is 3562 bp in length, some tandem repeat sequences, conserved elements (CSB1-3) and termination associated sequences (TAS1-3) were found in the control region.

Complete mitochondrial genome of Lacerta agilis (Squamata, Lacertidae).

The complete mitochondrial genome sequence of Lacerta agilis was determined in the present paper. The genome was 17,090 bp in length and contained 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and 1 control region (CR). The gene composition and order of which was similar to most other Squamate reptiles. The overall base composition of the genome in descending order was 31.29% A, 26. 39% C, 29.01% T and 13.29% G, with a slight AT bias of 60.30%. CR is located between the tRNA-Pro and tRNA-Phe genes and is 1688 bp in length, some tandem repeat sequences and conserved elements (CSB1-3) were found in the control region.

The influence of dispositional optimism on decision regret to undergo major breast reconstructive surgery.

BACKGROUND & OBJECTIVES: It is not known if optimism influences regret following major reconstructive breast surgery. We examined the relationship between dispositional optimism, major complications and decision regret in patients undergoing microsurgical breast reconstruction. METHODS: A consecutive series of 290 patients were surveyed. Independent variables were: (1) dispositional optimism and (2) major complications. The primary outcome was Decision Regret. A multivariate regression analysis determined the relationship between the independent variables, confounders and decision regret. RESULTS: Of the 181 respondents, 63% reported no regret after breast reconstruction, 26% had mild regret, and 11% moderate to severe regret. Major complications did not have a significant effect on decision regret, and the impact of dispositional optimism was not significant in Caucasian women. There was a significant effect in non-Caucasian women with less optimism who had significantly higher levels of mild regret 1.36 (CI 1.02-1.97) and moderate to severe regret 1.64 (CI 1.0-93.87). CONCLUSIONS: This is the first paper to identify a subgroup of non-Caucasian patients with low dispositional optimism who may be at risk for developing regret after microsurgical breast reconstruction. Possible strategies to ameliorate regret may involve addressing cultural and language barriers, setting realistic expectations, and providing more support during the pre-operative decision-making phase.

Complete mitochondrial genome of Gekko swinhonis (Squamata, Gekkonidae).

The complete mitochondrial genome sequence of Gekko swinhonis was determined in this paper. The genome was 16,818 bp in length and contained 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and 1 control region (CR). The gene composition and order of G. swinhonis were similar to most other squamate reptiles. The overall base composition of the genome in descending order was 31.35% A, 27. 71% C, 26.28% T, and 14.67% G, with a slight AT bias of 57.62%. CR is located between the tRNA-Pro and tRNA-Phe genes and is 1456 bp in length; some tandem repeat sequences and conserved elements (TAS, CSB1-3) were found in the CR.

Complete mitochondrial genome of Kallima inachus (Lepidoptera: Nymphalidae: Nymphalinae): comparison of K. inachus and Argynnis hyperbius.

In this paper, we sequenced the complete mitochondrial genome of Kallima inachus (Lepidoptera: Nymphalidae: Nymphalinae), which is considered a rare species in China. The genome is 15,183 bp in size. Its gene arrangement pattern was identical with those of Argynnis hyperbius. We compared the mitochondrial genome of K. inachus with that of A. hyperbius. Nucleotide sequence similarity between the two whole mitochondrial genomes was 85.92%, and the relatively low similarity seems to indicate that the two species are distinctly separated on the species level. The information on the mitochondrial genome comparison of the two species is discussed in detail in this paper.

Complete mitochondrial genome of Shinisaurus crocodilurus (Squamata: Shinisaurus) and its genetic relationship with related species.

The 16,585 base pairs mitochondrial genome of Shinisaurus crocodilurus was determined by using PCR amplification and DNA sequencing. To determine the phylogenetic position of S. crocodilurus with related species within Squamata, the phylogenetic tree was reconstructed with the concatenated nucleotide sequences of the 12 heavy-strand-encoded protein genes. Phylogenetic analyses based on maximum parsimony and Bayesian inference methods consistently support that the S. crocodilurus was closely related to the Helodermatidae within a monophyletic Anguimorpha group. And the result here contradicted the monophyly of Varanoidea (Varanidae + Helodermatidae). In addition, the Gekkonidae was found to possess a basal phylogenetic position within squamata and the traditional hypothesis of monophyletic lineages of Iguania and Scleroglossa was not supported in this study.

Genetic variation and differentiation of Gekko gecko from different populations based on mitochondrial cytochrome b gene sequences and karyotypes.

Black-spotted and red-spotted tokay geckos are distributed in different regions and have significant differences in morphological appearance, but have been regarded as the same species, Gekko gecko, in taxonomy. To determine whether black-spotted and red-spotted tokay geckos are genetically differentiated, we sequenced the entire mitochondrial cytochrome b gene (1147 bp) from 110 individuals of Gekko gecko collected in 11 areas including Guangxi China, Yunnan China, Vietnam, and Laos. In addition, we performed karyotypic analyses of black-spotted tokay geckos from Guangxi China and red-spotted tokay geckos from Laos. These phylogenetic analyses showed that black-spotted and red-spotted tokay geckos are divided into two branches in molecular phylogenetic trees. The average genetic distances are as follows: 0.12-0.47% among six haplotypes in the black-spotted tokay gecko group, 0.12-1.66% among five haplotypes in the red-spotted tokay gecko group, and 8.76-9.18% between the black-spotted and red-spotted tokay geckos, respectively. The karyotypic analyses showed that the karyotype formula is 2n = 38 = 8m + 2sm + 2st + 26t in red-spotted tokay geckos from Laos compared with 2n = 38 = 8m + 2sm + 28t in black-spotted tokay geckos from Guangxi China. The differences in these two kinds of karyotypes were detected on the 15th chromosome. The clear differences in genetic levels between black-spotted and red-spotted tokay geckos suggest a significant level of genetic differentiation between the two.

The complete mitochondrial genome of Chrysolophus pictus (Galliformes: Phasianidae) and a phylogenetic analysis with related species.

The 16,678 bp mitochondrial genome of the Chrysolophus pictus has been sequenced in this paper. To determine the phylogentic position of C. pictus with related species within Phasianidae, the phylogenetic tree was reconstructed with the concatenated nucleotide dataset of the 12 heavy-strand-encoded protein genes. The phylogenetic analysis was carried out using maximum parsimony (MP) and Bayesian inference (BI) methods. MP and BI phylogenetic trees here showed similar topology and consistently suggested that C. pictus shared a close relationship with Phasianus versicolor. The results also showed that the Meleagris gallopavo possessed a basal phylogenetic position within Phasianidae, which may imply that it should be classified into the Phasianidae.

Complete mitochondrial genome of the red-spotted tokay gecko (Gekko gecko, Reptilia: Gekkonidae): comparison of red- and black-spotted tokay geckos.

Here, we sequenced the complete mitochondrial genome of the red-spotted tokay gecko (Squamata: Gekkonidae). The genome is 16,590 bp in size. Its gene arrangement pattern was identical with that of black-spotted tokay gecko. We compared the mitochondrial genome of red-spotted tokay gecko with that of the black-spotted tokay gecko. Nucleotide sequence of the two whole mitochondrial genomes was 97.99% similar, and the relatively high similarity seems to indicate that they may be separated at the subspecies level. The information of mitochondrial genome comparison of the two morphological types of tokay gecko is discussed in detail.