Nuclear-Targeting Lipid PtIV Prodrug Amphiphile Cooperates with siRNA for Enhanced Cancer Immunochemotherapy by Amplifying Pt-DNA Adducts and Reducing Phosphatidylserine Exposure.

Patients treated with Pt-based anticancer drugs (PtII) often experience severe side effects and are susceptible to cancer recurrence due to the limited bioavailability of PtII and tumor-induced immunosuppression. The exposure of phosphatidylserine on the cell's outer surface induced by PtII results in profound immunosuppression through the binding of phosphatidylserine to its receptors on immune cells. Here, we report a novel approach for enhanced cancer chemoimmunotherapy, where a novel nuclear-targeting lipid PtIV prodrug amphiphile was used to deliver a small interfering RNA (siXkr8) to simultaneously amplify Pt-DNA adducts and reduce the level of exposure of phosphatidylserine. This drug delivery vehicle is engineered by integrating the PtIV prodrug with self-assembly performance and siXkr8 into a lipid nanoparticle, which shows tumor accumulation, cancer cell nucleus targeting, and activatable in a reduced microenvironment. It is demonstrated that nuclear-targeting lipid PtIV prodrug increases the DNA cross-linking, resulting in increased Pt-DNA adduct formation. The synergistic effects of the PtIV prodrug and siXkr8 contribute to the improvement of the tumor immune microenvironment. Consequently, the increased Pt-DNA adducts and immunogenicity effectively inhibit primary tumor growth and prevent tumor recurrence. These results underscore the potential of utilizing the nuclear-targeting lipid PtIV prodrug amphiphile to enhance Pt-DNA adduct formation and employing siXkr8 to alleviate immunosuppression during chemotherapy.

Waste to treasure: Electrocatalytic upcycling of n-valeraldehyde to octane by Zn-Co bimetallic oxide with atomic level cation defect.

n-Valeraldehyde is widely used in organic synthesis field as an important intermediate and feedstock, which makes it a significant class of environmental pollutants. In view of the high poisonous and harmful of n-valeraldehyde to human health and ecological environment, it is important to develop green and sustainable technology to reduce the pollution of n-valeraldehyde. In this work, electrocatalytic n-valeraldehyde oxidation using Zn-Co bimetallic oxides was applied to control n-valeraldehyde contamination and highly valuable octane production. To further improve the performance of Zn-Co bimetallic oxides, atomic level Zn vacancies were created across the Zn-Co bimetallic oxides (dx-ZnCo2O4) by post-etching and oxygen vacancy filling methods. Electrochemical experiments results showed that dx-ZnCo2O4 owned a much higher octane yield (1193.4 µmol g-1 h-1) and octane selectivity (octane/butene ≈10). Theoretical calculations demonstrated that the introduction of atomic level Zn vacancies in Zn-Co bimetallic oxide changed the electronic distribution around O, Co and Zn atoms, resulted in an alteration in n-valeraldehyde adsorption sites from Co to Zn, reduced the formation barrier of key intermediate *C4H9 and facilitated the transfer of n-valeraldehyde to octane. This study provides a new idea for the development of high-performance electrocatalysts for controlling n-valeraldehyde pollution.

Morusinol Extracted from Morus alba Inhibits Cell Proliferation and Induces Autophagy via FOXO3a Nuclear Accumulation-Mediated Cholesterol Biosynthesis Obstruction in Colorectal Cancer.

The incidence rate of colorectal cancer (CRC) has been increasing significantly in recent years, and it is urgent to develop novel drugs that have more effects for its treatment. It has been reported that many molecules extracted from the root bark of Morus alba L. (also known as Cortex Mori) have antitumor activities. In our study, we identified morusinol as a promising anticancer agent by selecting from 30 molecules extracted from Morus alba L. We found that morusinol treatment suppressed cell proliferation and promoted apoptosis of CRC cells in vitro. Besides this, we observed that morusinol induced cytoprotective autophagy. The GO analysis of differentially expressed genes from RNA-seq data showed that morusinol affected cholesterol metabolism. Then we found that key enzyme genes in the cholesterol biosynthesis pathway as well as the sterol regulatory element binding transcription factor 2 (SREBF2) were significantly downregulated. Furthermore, additional cholesterol treatment reversed the anti-CRC effect of morusinol. Interestingly, we also found that morusinol treatment could promote forkhead box O3 (FOXO3a) nuclear accumulation, which subsequently suppressed SREBF2 transcription. Then SREBF2-controlled cholesterol biosynthesis was blocked, resulting in the suppression of cell proliferation, promotion of apoptosis, and production of autophagy. The experiments in animal models also showed that morusinol significantly impeded tumor growth in mice models. Our results suggested that morusinol may be used as a candidate anticancer drug for the treatment of CRC.

Visualization of the elevated levels of hypochlorous acid in Alzheimer's disease with a ruthenium(II) complex-based luminescence probe.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder that devastatingly affects people's lives. Accumulating evidence indicates that the pathological progression of AD is inseparably connected with hypochlorous acid (HClO). However, further exploring the biological function remains an open challenging due to a lack of effective tools to image HClO in AD brains. To this end, a ruthenium(II) luminescence probe, Ru-HClO, is developed for quantitative detection and visualization of HClO in nerve cells and AD brains. Ru-HClO shows quenched luminescence due to the PET process (excited electron transfer from Ru(II) center to diaminomaleonitrile) and the CN bond isomerization in the excited state. The HClO-triggered specific cleavage reaction with Ru-HClO cleaves the CN bond to form highly luminescent Ru-COOH. Ru-HClO shows rapid response speed, high sensitivity and selectivity, excellent biocompatibility, which makes the probe to be applied to semi-quantitative analysis of HClO in nerve cells and high-throughput screening of anti-AD drugs in the AD cell model. Moreover, using Ru-HClO as a probe, present work further validated that the elevated levels of HClO secretion were accompanied by the AD progressed. These findings may provide valuable results for figuring out the biological roles that HClO played in AD but also for accelerating anti-AD therapeutic discovery.

AKIP1 accelerates glioblastoma progression through stabilizing EGFR expression.

A Kinase Interacting Protein 1 (AKIP1) is found to be overexpressed in a variety of human cancers and associated with patients' worse prognosis. Several studies have established AKIP1's malignant functions in tumor metastasis, angiogenesis, and chemoradiotherapy resistance. However, the mechanism of AKIP1 involved in accelerating glioblastoma (GBM) progression remains unknown. Here, we showed that the expression of AKIP1 was positively correlated with the glioma pathological grades. Down-regulating AKIP1 greatly impaired the proliferation, colony formation, and tumorigenicity of GBM cells. In terms of the mechanism, AKIP1 cooperates with transcriptional factor Yin Yang 1 (YY1)-mediated Heat Shock Protein 90 Alpha Family Class A Member 1 (HSP90AA1) transcriptional activation, enhancing the stability of Epidermal Growth Factor Receptor (EGFR). YY1 was identified as a potential transcriptional factor of HSP90AA1 and directly interacts with AKIP1. The overexpression of HSP90α significantly reversed AKIP1 depletion incurred EGFR instability and the blocked cell proliferation. Moreover, we further investigated the interacted pattern between EGFR and HSP90α. These findings established that AKIP1 acted as a critical oncogenic factor in GBM and uncovered a novel regulatory mechanism in EGFR aberrant expression.

Ratiometric lysosome-targeting luminescent probe based on a coumarin-ruthenium(II) complex for formaldehyde detection and imaging in living cells and mouse brain tissues.

Ratiometric luminescence probes have attracted widespread attention because of their self-calibration capability. However, some defects, such as small emission shift, severe spectral overlap and poor water solubility, limit their application in the field of biological imaging. In this study, a unique luminescence probe, Ru-COU, has been developed by combining tris(bipyridine)ruthenium(II) complex with coumarin derivative through a formaldehyde-responsive linker. The probe exhibited a large emission shift (Δλ > 100 nm) and good water solubility, achieving ratiometric emission responses at 505 nm and 610 nm toward formaldehyde under acidic conditions. Besides, ratiometric luminescence imaging of formaldehyde in living cells and Alzheimer disease mouse's brain slices demonstrates the potential value of Ru-COU for the diagnosis and treatment of formaldehyde related diseases.

Efficiency co-delivery of ellagic acid and oxygen by a non-invasive liposome for ameliorating diabetic retinopathy.

Diabetic retinopathy (DR) is one of the serious complications of diabetes, which has become the fourth leading cause of vision loss worldwide. Current treatment of DR relies on intravitreal injections of antiangiogenic agents, which has made considerable achievements in reducing visual impairment. However, long-term invasive injections require advanced technology and can lead to poor patient compliance as well as the incidence of ocular complications including bleeding, endophthalmitis, retinal detachment and others. Hence, we developed non-invasive liposomes (EA-Hb/TAT&isoDGR-Lipo) for efficiency co-delivery of ellagic acid and oxygen, which can be administered intravenously or by eye drops. Among that, ellagic acid (EA), as an aldose reductase inhibitor, could remove excessive reactive oxygen species (ROS) induced by high glucose for preventing retinal cell apoptosis, as well as reduce retinal angiogenesis through the blockage of VEGFR2 signaling pathway; carried oxygen could ameliorate DR hypoxia, and further enhanced the anti-neovascularization efficacy. Our results showed that EA-Hb/TAT&isoDGR-Lipo not only effectively protected retinal cells from high glucose-induced damage, but also inhibited VEGF-induced vascular endothelial cells migration, invasion, and tube formation in vitro. In addition, in a hypoxic cell model, EA-Hb/TAT&isoDGR-Lipo could reverse retinal cell hypoxia, thereby reducing the expression of VEGF. Significantly, after being administered as an injection or eye drops, EA-Hb/TAT&isoDGR-Lipo obviously ameliorated the structure (central retinal thickness and retinal vascular network) of retina by eliminating ROS and down-regulating the expression of GFAP, HIF-1α, VEGF and p-VEGFR2 in a DR mouse model. In summary, EA-Hb/TAT&isoDGR-Lipo holds great potentials in improvement of DR, which provides a novel approach for the treatment of DR.

Novel Airflow-Field-Driven Melt Spinning 3D Printing of Tubular Scaffolds Based on Polycaprolactone Blends.

The fabrication of various 3D tissue engineering tubular scaffolds with fibrous structures, to assist the human body in rapidly repairing a variety of ailments, is receiving more and more attention. Due to the inefficiency of the majority of fibrous preparation techniques, the question of how to rapidly produce the requisite three-dimensional tubular microfiber scaffold structures has become an urgent problem. In this study, an efficient polymer fiber preparation method was developed, using a high-speed airflow drive. Melt blending of polycaprolactone (PCL), polylactic acid (PLA), and tributyl citrate (TBC), was used for the printing material, to achieve the efficient preparation of tubular microfiber scaffolds with different structures. The scaffold diameter was as small as 2 mm, the wall thickness was up to 100 µm, and the fiber injection efficiency reached 15.48 g/h. By utilizing simulations to optimize the printing parameters and by adjusting the printing settings, it was possible to achieve a controlled fiber diameter in the range of 3 µm to 15 µm. In addition, plasma treatment was applied to the microfibers' surface, to increase their wettability, and the efficiency of the hydrophilic modification was demonstrated. Furthermore, the mechanical property test demonstrated that the fibers have a tensile strength of 1.36 ± 0.16 MPa and a tensile strain of 30.8 ± 3.5%. The radial compressive strain of the tubular scaffold could reach 60% of the original scaffold's diameter. Finally, the in vitro degradation of the fibers at various pH values was tested. The results showed that, under alkaline conditions, the surface of the fibers would be severely crushed and the rate of deterioration would increase.

Morusinol extracted from Morus alba induces cell cycle arrest and apoptosis via inhibition of DNA damage response in melanoma by CHK1 degradation through the ubiquitin-proteasome pathway.

BACKGROUD: Flavonoids have a variety of biological activities, such as anti-inflammation, anti-tumor, anti-thrombosis and so on. Morusinol, as a novel isoprene flavonoid extracted from Morus alba root barks, has the effects of anti-arterial thrombosis and anti-inflammatory in previous studies. However, the anti-cancer mechanism of morusinol remains unclear. PURPOSE: In present study, we mainly studied the anti-tumor effect of morusinol and its mode of action in melanoma. METHODS: The anti-cancer effect of morusinol on melanoma were evaluated by using the MTT, EdU, plate clone formation and soft agar assay. Flow cytometry was used for detecting cell cycle and apoptosis. The É£-H2AX immunofluorescence and the alkaline comet assay were used to detect DNA damage and the Western blotting analysis was used to investigate the expressions of DNA-damage related proteins. Ubiquitination and turnover of CHK1 were also detected by using the immunoprecipitation assay. The cell line-derived xenograft (CDX) mouse models were used in vivo to evaluate the effect of morusinol on tumorigenicity. RESULTS: We demonstrated that morusinol not only had the ability to inhibit cell proliferation, but also induced cell cycle arrest at G0/G1 phase, caspase-dependent apoptosis and DNA damage in human melanoma cells. In addition, morusinol effectively inhibited the growth of melanoma xenografts in vivo. More strikingly, CHK1, which played an important role in maintaining the integrity of cell cycle, genomic stability and cell viability, was down-regulated in a dose- and time-dependent manner after morusinol treatment. Further research showed that CHK1 was degraded by the ubiquitin-proteasome pathway. Whereafter, morusinol-induced cell cycle arrest, apoptosis and DNA damage were partially salvaged by overexpressing CHK1 in melanoma cell lines. Herein, further experiments demonstrated that morusinol increased the sensitivity of dacarbazine (DTIC) to chemotherapy for melanoma in vitro and in vivo. CONCLUSION: Morusinol induces CHK1 degradation through the ubiquitin-proteasome pathway, thereby inducing cell cycle arrest, apoptosis and DNA damage response in melanoma. Our study firstly provided a theoretical basis for morusinol to be a candidate drug for clinical treatment of cancer, such as melanoma, alone or combinated with dacarbazine.

Combined bulk RNA-seq and single-cell RNA-seq identifies a necroptosis-related prognostic signature associated with inhibitory immune microenvironment in glioma.

Necroptosis is a programmed cell death playing a significant role in cancer. Although necroptosis has been related to tumor immune environment (TIME) remodeling and cancer prognosis, however, the role of necroptosis-related genes (NRGs) in glioma is still elusive. In this study, a total of 159 NRGs were obtained, and parameters such as mutation rate, copy number variation (CNV), and relative expression level were assessed. Then, we constructed an 18-NRGs-based necroptosis-related signature (NRS) in the TCGA dataset, which could predict the patient's prognosis and was validated in two external CGGA datasets. We also explored the correlation between NRS and glioma TIME, chemotherapy sensitivity, and certain immunotherapy-related factors. The two necroptosis-related subtypes were discovered and could also distinguish the patients' prognosis. Through the glioblastoma (GBM) scRNA-seq data analysis, NRGs' expression levels in different GBM patient tissue cell subsets were investigated and the relative necroptosis status of different cell subsets was assessed, with the microglia score culminating among all. Moreover, we found a high infiltration level of immunosuppressive cells in glioma TIME, which was associated with poor prognosis in the high-NRS glioma patient group. Finally, the necroptosis suppressor CASP8 exhibited a high expression in glioma and was associated with poor prognosis. Subsequent experiments were performed in human glioma cell lines and patients' tissue specimens to verify the bioinformatic analytic findings about CASP8. Altogether, this study provides comprehensive evidence revealing a prognostic value of NRGs in glioma, which is associated with TIME regulation.

A Ruthenium(II) complex-based probe for colorimetric and luminescent detection and imaging of hydrogen sulfide in living cells and organisms.

The development of reliable bioanalytical probes for sensitive and specific detection of hydrogen sulfide (H2S) plays important role for better understanding the roles of this biomolecule in living cells and organisms. Taking advantages of unique photophysical properties of ruthenium(II) (Ru(II)) complex, this work presents the development of a responsive Ru(II) complex probe, Ru-PNBD, for colorimetric and luminescent analysis of H2S in living cells and organisms. In aqueous solution, Ru-PNBD is yellow color and non-luminescent because of the photoinduced electron transfer (PET) process from Ru(II) complex luminophore to NBD moiety. The H2S-triggered specific nucleophilic substitution reaction with Ru-PNBD cleaves the NBD moiety to form pink NBD-SH and highly luminescent Ru-PH. The color of the solution thus changes from yellow to pink for colorimetric analysis and the emission intensity is about 65-fold increased for luminescent analysis. Ru-PNBD has high sensitivity and selectivity for H2S detection, low cytotoxicity and good permeability to cell membrane, which allow the application of this probe for H2S imaging in living cells, Daphnia magna, and larval zebrafish. Collectively, this work provides a useful tool for H2S analysis and expands the scope of transition metal complex probes.

New insights into the links between anti-diabetes drugs and gut microbiota.

In patients with type 2 diabetes mellitus (T2DM), the intestinal flora is out of balance and accompanied by leaky gut. The flora is characterized by an increase in mucus-degrading bacteria and a decrease in fiber-degrading bacteria. Short-chain fatty acids (SCFAs), as the major fiber-degrading bacteria fermentation, not only ameliorate the leaky gut, but also activate GPR43 to increase the mass of functional pancreatic ß-cells and exert anti-inflammation effect. At present, the gut microbiota is considered as the potential target for anti-diabetes drugs, and how to reverse the imbalance of gut microbiota has become a therapeutic strategy for T2DM. This review briefly summarizes the drugs or compounds that have direct or potential therapeutic effects on T2DM by modulating the gut microbiota, including biguanides, isoquinoline alkaloids, stilbene and C7N-aminocyclic alcohols.

Piperine ameliorates insulin resistance via inhibiting metabolic inflammation in monosodium glutamate-treated obese mice.

BACKGROUND: Metabolic inflammation is an essential event in obesity-induced diabetes and insulin resistance. In obesity, an increasing number of macrophages recruited into visceral adipose tissues undergo significant M1-like polarization, secreting variable amounts of pro-inflammatory cytokines and causing insulin resistance. Piperine has excellent anti-inflammatory activities and may be used in the treatment of a variety of inflammatory diseases. In this study, we investigated the effect of piperine on adipose tissue inflammation and insulin resistance in obese mice. METHODS: Newborn mice were subcutaneously (s.c.) injected with monosodium glutamate (MSG) to establish a diabetes model. After 24 weeks, the MSG obese mice were divided into three groups and treated with piperine (40 mg/kg/day), metformin (150 mg/kg/day) and vehicle for 10 successive weeks, respectively. RESULTS: The obesity model was successfully established, as the body weight, insulin resistance, fasting blood glucose (FBG) and dyslipidemia were significantly increased. The 10-week administration of piperine to the obese mice not only significantly decreased the elevated FBG (Model: 6.45 ± 0.41 mM; Piperine: 4.72 ± 0.44 mM, p < 0.01), serum TC (Model: 5.66 ± 0.66 mM; Piperine: 3.55 ± 0.30 mM, p < 0.01) and TG (Model: 1.41 ± 0.08 mM; Piperine: 0.94 ± 0.05 mM, p < 0.001), but also enhanced the glucose infusion rate in the hyperglycemic clamp experiment. Meanwhile, piperine improved glucose intolerance and insulin resistance in MSG obese mice. Piperine markedly decreased the total and differential white blood cell (WBC) count, the serum levels of lipopolysaccharide (LPS) and pro-inflammatory cytokines such as galectin-3 (Gal-3) and interleukin-1ß (IL-1ß). Furthermore, piperine clearly down-regulated the mRNA levels of pro-inflammatory cytokines and the protein levels of M1-like polarization marker CD11c and Gal-3 in adipose tissues. The in vitro study showed that piperine inhibited LPS-stimulated polarization of RAW 264.7 cells toward the M1 phenotype. CONCLUSIONS: Piperine served as an immunomodulator for the treatment of obesity-related diabetes through its anti-inflammatory effects, which might be achieved by inhibiting macrophages M1 polarization in adipose tissues.

Tumor-targetable magnetoluminescent silica nanoparticles for bimodal time-gated luminescence/magnetic resonance imaging of cancer cells in vitro and in vivo.

Bimodal photoluminescence-magnetic resonance (MR) imaging technique has attracted tremendous attention due to its great potential in biomedical researches and clinical practices. Herein a novel multifunctional magnetoluminescent nanocomposite, FA-Gd-Tb@SiO2, was found to serve as an effective probe for bimodal time-gated luminescence/MR imaging of cancer cells in vitro and in vivo. The nanoprobe was designed by integrating a luminescent Tb3+ complex, a Gd(III)-based contrast agent and a tumor-targeting molecule, folic acid (FA), into a silica nanoparticle. The integration of these functional moieties allows the nanoprobe to be employed for specific imaging of cancer cells with background-free TGL and non-invasive MR imaging modes. In addition, the optical and magnetic properties were dramatically improved after implicating the newly synthesized nanoarchitecture. In vitro cellular TGL imaging demonstrated that the FA-Gd-Tb@SiO2 nanoprobe could recognize and accumulate in cancer cells overexpressing FA receptor. Furthermore, in vivo study revealed that the as-prepared nanoprobe was able to effectively enhance T1-weighted MR contrast and TGL intensity in tumor tissue, which might contribute to the precise detection and tracing of cancer cells, as well as diagnosis and therapy of tumor in clinical.

"Two Birds with One Stone" Ruthenium(II) Complex Probe for Biothiols Discrimination and Detection In Vitro and In Vivo.

In this work, a "two birds with one stone" ruthenium(II) complex probe, Ru-NBD, is proposed as an effective tool for biothiols detection and discrimination in vitro and in vivo. Ru-NBD is nonluminescent due to the quenching of Ru(II) complex emission by photoinduced electron transfer (PET) from Ru(II) center to NBD and the quenching of NBD emission through 4-substitution with "O" ether bond. Ru-NBD is capable of reacting with Cys/Hcy to form long-lived red-emitting Ru-OH and short-lived green-emitting NBD-NR, while reacting with GSH to produce Ru-OH and nonemissive NBD-SR. The long lifetime emission of Ru(II) complex allows elimination of short lifetime background and NBD-NR fluorescence for total biothiols detection ("bird" one) by time-gated luminescence (TGL) analysis, and the remarkable difference in luminescence color response allows discrimination GSH and Cys/Hcy ("bird" two) through steady-state luminescence analysis. Ru-NBD features high sensitivity and selectivity, rapid luminescence response, and low cytotoxicity, which enables it to be used as the probe for luminescence and background-free TGL detection and visualization of biothiols in live cells, zebrafish, and mice. The successful development of this probe is anticipated to contribute to the future biological studies of biothiols roles in various diseases.

Genome-wide analysis of NDR1/HIN1-like genes in pepper (Capsicum annuum L.) and functional characterization of CaNHL4 under biotic and abiotic stresses.

Plant NDR1/HIN1-like (NHL) genes play an important role in triggering plant defenses in response to biotic stresses. In this study, we performed a genome-wide identification of the NHL genes in pepper (Capsicum annuum L.) and characterized the functional roles of these CaNHL genes in response to abiotic stresses and infection by different pathogens. Phylogenetic analysis revealed that CaNHLs can be classified into five distinct subgroups, with each group containing generic and specific motifs. Regulatory element analysis showed that the majority of the promoter regions of the identified CaNHLs contain jasmonic acid (JA)-responsive and salicylic acid (SA)-responsive elements, and transcriptomic analysis revealed that CaNHL genes are expressed in all the examined tissues of pepper. The CaNHL1, CaNHL4, CaNHL6, CaNHL10, CaNHL11, and CaNHL12 genes were significantly upregulated under abiotic stress as well as in response to different pathogens, such as TMV, Phytophthora capsici and Pseudomonas syringae. In addition, we found that CaNHL4 localizes to the plasma membrane. CaNHL4-silenced pepper plants display significantly increased susceptibility to TMV, Phytophthora capsici and Pseudomonas syringae, exhibiting reduced expression of JA-related and SA-related genes and reduced ROS production. However, transient overexpression of CaNHL4 in pepper increases the expression of JA-related and SA-related genes, enhances the accumulation of ROS, and inhibits the infection of these three pathogens. Collectively, for the first time, we identified the NHL genes in pepper and demonstrated that CaNHL4 is involved in the production of ROS and that it also regulates the expression of JA-related and SA-related genes in response to different pathogens, suggesting that members of the CaNHL family play an essential role in the disease resistance of pepper.

Responsive ruthenium complex probe for phosphorescence and time-gated luminescence detection of bisulfite.

Sensitive and selective quantification of specific analytes is of great significance in analytical and environmental sciences, as well as in the food industry. Herein, we report the design, synthesis, characterization, and application of a responsive ruthenium(ii) complex probe, Ru-azo, for phosphorescence and time-gated luminescence (TGL) detection of bisulfite, an important additive in the food industry. Upon a specific nucleophilic addition reaction between bisulfite and the azo group of Ru-azo, a new ruthenium(ii) complex, Ru-SO3, was obtained, which resulted in a remarkable increase in phosphorescence intensity, allowing the bisulfite detection to be achieved. In addition, long-lived emissions of Ru-azo (τ = 258 ns) and Ru-SO3 (τ = 261 ns) also enabled the TGL detection of bisulfite in autofluorescence-rich food samples. Through theoretical computations, the photoinduced electron transfer (PET) process within the ruthenium(ii) complex was validated, which unveiled the rationality of the luminescence "off-on" response of Ru-azo to bisulfite. The probe showed advantages of good water solubility, and high sensitivity, selectivity and accuracy for responding to bisulfite, facilitating its application in phosphorescence and TGL detection of bisulfite in aqueous and food samples.

Identification of differentially expressed protein-coding genes in lung adenocarcinomas.

Lung adenocarcinoma accounts for a high proportion of lung cancers. Though efforts have been made to develop new and effective treatments for this disease, the mortality rate remains high. Gene expression microarrays facilitate the study of lung cancer at the molecular level. The present study aimed to detect differentially expressed protein-coding genes to identify novel biomarkers and therapeutic targets for lung adenocarcinoma. Aberrations in gene expression in lung adenocarcinoma were determined by analysis of mRNA microarray datasets from the Gene Expression Omnibus database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein-protein interaction (PPI) networks and statistical analysis were used to identify the biological functions of the differentially expressed genes (DEGs). The results of the bioinformatics analysis were subsequently validated using reverse transcription-quantitative PCR. A total of 303 DEGs were identified in lung adenocarcinomas, and they were enriched in a number of cancer-associated GO terms and KEGG pathways. DNA topoisomerase 2α (TOP2A), cell division cycle protein homolog 20 (CDC20), mitotic checkpoint serine/threonine protein kinase BUB1 (BUB1) and mitotic spindle assembly checkpoint protein MAD2A (MAD2L1) exhibited the highest degree of interaction in the PPI network. Survival analysis performed using Kaplan-Meier curves and Cox regression indicated that these four genes were all significantly associated with the survival of patients with lung adenocarcinomas. In conclusion, TOP2A, CDC20, BUB1 and MAD2L1 may be key protein-coding genes that may serve as biomarkers and therapeutic targets in lung adenocarcinomas.

Key roles of Rho GTPases, YAP, and Mutant P53 in anti-neoplastic effects of statins.

Emerging epidemiological and preclinical studies have focused on statins and mevalonate pathway to identify potential therapeutic target and clarify the underlying mechanism of the anti-neoplastic effects. Reductions of mevalonate or isoprenoids, caused by statins, would further decrease the isoprenylation of Rho GTPases which is the crucial step for Rho GTPases to anchor on inner cellular membrane. Following anchoring, activated Rho GTPases can mediate a series of cellular activities such as cytoskeleton reprogramming, front-rear polarity, and cell-ECM adhesion. These changes not only facilitate tumor cell detachment and migration but also bring great mechanical changes to directly activate YAP, the major nuclear mechanotransducer, to translocate into nucleus. Recently, statins have been identified as potent inhibitors of YAP. Once entering nucleus, YAP would combine TEADs to promote the transcription of about 100 genes, which are involved in cell proliferation, cell cycle regulation, stemness, invasion, and metastasis. Besides, statins are able to promote the degradation of misfolded mutant p53 (mutp53), which is an oncogene in a variety of human malignancies. Reduction in mevalonate-5-phosphate (MVP), also induced by statins, would impair the stability of DNAJA1-mutp53 complex; then, elevated C terminus of Hsc70-interacting protein (CHIP) mediates the nuclear export and degradation of misfolded mutp53 through ubiquitin-proteasome pathway. It is worth noted that YAP, mutp53, and mevalonate pathway form two positive feedback loops. It is reasonable to believe that Rho GTPases, YAP, and mutp53 are determinants for statins as anti-cancer agents: tumor cells harboring mutp53 and nuclear-located YAP would be more sensitive to statins.

A folic acid-functionalized dual-emissive nanoprobe for "double-check" luminescence imaging of cancer cells.

Development of luminescent probes for rapid and effective discrimination and detection of cancer cells has the potential to address the current challenges in early diagnosis and treatment monitoring of cancer diseases. In this work, we report the preparation of a unique folic acid (FA)-functionalized dual-emissive nanoprobe, CTMR@BHHBCB-Eu-FA, for steady-state and time-gated luminescence "double-check" imaging of cancer cells. The nanoprobe was engineered by covalently doping two luminescent dyes, 5-carboxytetramethylrhodamine (CTMR) and BHHBCB-Eu3+, in core and shell of silica nanoparticles, followed by surface modification of the nanoparticles with FA, a cancer cell-targeting molecule. As-prepared nanoprobe is monodisperse and highly stable in buffer displaying two strong emissions, short-lived emission from CTMR at 584 nm and long-lived emission from BHHBCB-Eu3+ at 612 nm. The nanoprobe is biocompatible, and can specifically recognize folate receptor (FR)-overexpressed cancer cells through the FA-FR binding interaction. Using the nanoprobe, the "double-check" imaging of HeLa cells was successfully achieved at steady-state and time-gated luminescence modes, indicating the capability of the nanoprobe for cancer cell imaging.