A Platinum-Aluminum Bimetallic Salen Complex for Pro-senescence Cancer Therapy.

Cell senescence is defined as irreversible cell cycle arrest, which can be triggered by telomere shortening or by various types of genotoxic stress. Induction of senescence is emerging as a new strategy for the treatment of cancer, especially when sequentially combined with a second senolytic drug capable of killing the resulting senescent cells, however severely suffering from the undesired off-target side effects from the senolytic drugs. Here, we prepare a bimetalic platinum-aluminum salen complex (Alumiplatin) for cancer therapy-a combination of pro-senesence chemotherapy with in situ senotherapy to avoid the side effects. The aluminum salen moiety, as a G-quadruplex stabilizer, enhances the salen's ability to induce cancer cell senescence and this phenotype is in turn sensitive to the cytotoxic activity of the monofunctional platinum moiety. It exhibits an excellent capability for inducing senescence, a potent cytotoxic activity against cancer cells both in vitro and in vivo, and an improved safety profile compared to cisplatin. Therefore, Alumiplatin may be a good candidate to be further developed into safe and effective anticancer agents. This novel combination of cell senescence inducers with genotoxic drugs revolutionizes the therapy options of designing multi-targeting anticancer agents to improve the efficacy of anticancer therapies.

G-quadruplex inducer/stabilizer pyridostatin targets SUB1 to promote cytotoxicity of a transplatinum complex.

Pyridostatin (PDS) is a well-known G-quadruplex (G4) inducer and stabilizer, yet its target genes have remained unclear. Herein, applying MS proteomics strategy, we revealed PDS significantly downregulated 22 proteins but upregulated 16 proteins in HeLa cancer cells, of which the genes both contain a number of G4 potential sequences, implying that PDS regulation on gene expression is far more complicated than inducing/stabilizing G4 structures. The PDS-downregulated proteins consequently upregulated 6 proteins to activate cyclin and cell cycle regulation, suggesting that PDS itself is not a potential anticancer agent, at least toward HeLa cancer cells. Importantly, SUB1, which encodes human positive cofactor and DNA lesion sensor PC4, was downregulated by 4.76-fold. Further studies demonstrated that the downregulation of PC4 dramatically promoted the cytotoxicity of trans-[PtCl2(NH3)(thiazole)] (trans-PtTz) toward HeLa cells to a similar level of cisplatin, contributable to retarding the repair of 1,3-trans-PtTz crosslinked DNA lesion mediated by PC4. These findings not only provide new insights into better understanding on the biological functions of PDS but also implicate a strategy for the rational design of novel multi-targeting platinum anticancer drugs via conjugation of PDS as a ligand to the coordination scaffold of transplatin for battling drug resistance to cisplatin.

In Situ Reconstructed Zn doped Fex Ni(1- x ) OOH Catalyst for Efficient and Ultrastable Oxygen Evolution Reaction at High Current Densities.

Developing FeOOH as a robust electrocatalyst for high output oxygen evolution reaction (OER) remains challenging due to its low conductivity and dissolvability in alkaline conditions. Herein, it is demonstrated that the robust and high output Zn doped NiOOH-FeOOH (Zn-Fex Ni(1-x) )OOH catalyst can be derived by electro-oxidation-induced reconstruction from the pre-electrocatalyst of Zn modified Ni metal/FeOOH film supported by nickel foam (NF). In situ Raman and ex situ characterizations elucidate that the pre-electrocatalyst undergoes dynamic reconstruction occurring on both the catalyst surface and underneath metal support during the OER process. That involves the Fe dissolution-redeposition and the merge of Zn doped FeOOH with in situ generated NiOOH from NF support and NiZn alloy nanoparticles. Benefiting from the Zn doping and the covalence interaction of FeOOH-NiOOH, the reconstructed electrode shows superior corrosion resistance, and enhanced catalytic activity as well as bonding force at the catalyst-support interface. Together with the feature of superaerophobic surface, the reconstructed electrode only requires an overpotential of 330 mV at a high-current-density of 1000 mA cm-2 and maintains 97% of its initial activity after 1000 h. This work provides an in-depth understanding of electrocatalyst reconstruction during the OER process, which facilitates the design of high-performance OER catalysts.

Construction of MoS2@Activated Alumina Beads as Catalysts for Rapid Gold Recovery from Au(S2O3)23- Solution.

Gold recovery from thiosulfate leaching solution Au(S2O3)23- is regarded as a tough task because of the low efficiency and complex procedure in current technology, which hindered the industrial application of this eco-friendly technique. In this work, a MoS2@activated alumina bead composite (MoS2@AA) was constructed through a simple hydrothermal anchoring method and served as a catalyst to recover gold from Au(S2O3)23- solution for the first time. The microstructure and chemical component of MoS2@AA were systematically analyzed. In addition, batch experiments were carried out to explore the recovery behavior of Au(S2O3)23- (concentration: 10 to 200 ppm). Ascribing to the extraordinary optical property of MoS2@AA, Au(S2O3)23- could be directly reduced to Au0 by photogenerated electrons and then form a two-phase interface of gold/MoS2@AA. As a result, the recovery of Au(S2O3)23- can reach up to 98% on MoS2@AA, which was much higher than traditional methods. More importantly, the reduced Au0 could be desorbed from MoS2@AA through a supersonic method, achieving one-step Au0 recovery from Au(S2O3)23-. This novel strategy used in this research has great significance to the development of Au(S2O3)23- recovery in the future.

Depression, cognitive reserve markers, and dementia risk in the general population.

OBJECTIVES: We investigated depression, cognitive reserve, and their interaction as risk factors for incident dementia among community-dwelling older adults. METHODS: In total, 2099 participants, aged ≥65 years with no dementia during baseline assessment, who completed the follow-up two years later were included from the Cognitive Function and Ageing Study Wales. Baseline depression and dementia and dementia at follow-up were evaluated using the Geriatric Mental State Examination and the Automated Geriatric Examination for Computer Assisted Taxonomy. Cognitive reserve was measured by combining overall education, mid-life occupational complexity, and later-life social and cognitive activities. Risk of dementia in relation to depression and cognitive reserve was estimated using penalized maximum likelihood logistic regression. Interactions between cognitive reserve and depression were assessed using both multiplicative and additive scales. RESULTS: Baseline depression and low cognitive reserve significantly increased the risk of subsequent dementia at follow-up. No multiplicative interaction between cognitive reserve and depression existed. We observed an additive interaction between case-level depression and cognitive reserve. A significant association between depression and dementia was only found among people with low cognitive-reserve levels. CONCLUSIONS: Greater cognitive reserve attenuated the depression-associated risk of developing dementia. This suggests the need to emphasize prodromal dementia detection among older adults with lower cognitive reserve and depression.

Synergetic degradation of Methylene Blue through photocatalysis and Fenton reaction on two-dimensional molybdenite-Fe.

The greatest problem in conventional Fenton reaction is the slow production of ROS (reactive oxygen species) because of the inefficient Fe3+/Fe2+ conversion. Based on the extraordinary photo-response property of two-dimensional molybdenite (2DM), photogenerated electrons can be easy separated to accelerate the regeneration of Fe2+. In this work, Fe2+-anchored 2DM (2DM-Fe) was prepared and used as a heterogeneous Fenton catalyst to investigate the degradation efficiency to Methylene Blue (MB) in the presence of light. According to experimental results, 2DM-Fe exhibited extraordinary catalytic activity in MB elimination, which ascribed to the synergetic effect of photogenerated carriers and anchored Fe2+ to H2O2 activation. In addition, 2DM-Fe showed nearly 100% degradation efficiency to MB within 5 cycles with slight leaching amount of Mo and Fe ions, implying the strong stability and reusability in H2O2 system. Furthermore, the influences of H2O2 and 2DM-Fe dosages, pH values as well as the degradation efficiency to different dyes were also investigated. According to quenching experiments and EPR (electron paramagnetic resonance) test, the degradation mechanism of MB mainly ascribed to the oxidation of HO• and •O2-. This finding provides a novel strategy to design rational Fenton catalyst and has great significance to water remediation in the future.

Micromechanism in All-Solid-State Alloy-Metal Batteries: Regulating Homogeneous Lithium Precipitation and Flexible Solid Electrolyte Interphase Evolution.

Sulfide-based solid-state electrolytes (SSEs) matched with alloy anodes are considered as promising candidates for application in all-solid-state batteries (ASSBs) to overcome the bottlenecks of the lithium (Li) anode. However, an understanding of the dynamic electrochemical processes on alloy anode in SSE is still elusive. Herein, in situ atomic force microscopy gives insights into the block-formation and stack-accumulation behaviors of Li precipitation on an Li electrode, uncovering the morphological evolution of nanoscale Li deposition/dissolution in ASSBs. Furthermore, two-dimensional Li-indium (In) alloy lamellae and the homogeneous solid electrolyte interphase (SEI) shell on the In electrode reveal the precipitation mechanism microscopically regulated by the alloy anode. The flexible and wrinkle-structure SEI shell further enables the electrode protection and inner Li accommodation upon cycles, elucidating the functional influences of SEI shell on the cycling behaviors. Such on-site tracking of the morphological evolution and dynamic mechanism provide an in-depth understanding and thus benefit the optimizations of alloy-based ASSBs.

Cognitive reserve, modifiable-risk-factor profile and incidence of dementia: results from a longitudinal study of CFAS Wales.

OBJECTIVES: Both cognitive reserve and modifiable-risk-factor profiles play a role in dementia incidence. We investigated whether cognitive reserve moderates the risk of dementia attributable to the modifiable-risk-factor profile. METHOD: We followed 2102 older individuals aged 65+ years recruited from the population-based longitudinal cohort CFAS Wales study, begun in 2011, and the follow-up wave completed in early 2016. Cognitive reserve was measured by combining educational level, occupation complexity, and engagement in social and cognitive activities in later life. Modifiable-risk-factor profile scores were based on depression, diabetes, smoking, physical activity, healthy diet, and drinking. The interactions between cognitive reserve indicators and modifiable-risk-factor profiles were assessed on multiplicative and additive scales. RESULTS: There is an additive interaction between the composite effect of cognitive reserve indicator and modifiable-risk-factor profile on dementia. In those with low cognitive reserve, the risk of dementia in participants with a favorable profile was significantly lower than in those with an unfavorable one (OR = 0.08, 95% CI = 0.02-0.27). CONCLUSION: Cognitive reserve significantly moderates the association between modifiable-risk-factor profiles and dementia.

Dynamic Evolution of a Cathode Interphase Layer at the Surface of LiNi0.5Co0.2Mn0.3O2 in Quasi-Solid-State Lithium Batteries.

Intensive understanding of the surface mechanism of cathode materials, such as structural evolution and chemical and mechanical stability upon charging/discharging, is crucial to design advanced solid-state lithium batteries (SSLBs) of tomorrow. Here, via in situ atomic force microscopy monitoring, we explore the dynamic evolution process at the surface of LiNi0.5Co0.2Mn0.3O2 cathode particles inside a working SSLB. The dynamic formation process of the cathode interphase layer, with an inorganic-organic hybrid structure, was real-time imaged, as well as the evolution of its mechanical property by in situ scanning of the Derjaguin-Muller-Toporov modulus. Moreover, different components of the cathode interphase layer, such as LiF, Li2CO3, and specific organic species, were identified in detailat different stages of cycling, which can be directly correlated with the impedance buildup of the battery. In addition, the transition metal migration and the formation of new phases can further exacerbate the degradation of the SSLB. A relatively stable cathode interphase is key to improving the performance of SSLBs. Our findings provide deep insights into the dynamic evolution of surface morphology, chemical components and mechanical properties of the cathode interphase layer, which are pivotal for the performance optimization of SSLBs.

In Situ Visualization of Proteins in Single Cells by Time-of-Flight-Secondary Ion Mass Spectrometry Coupled with Genetically Encoded Chemical Tags.

In situ visualization of proteins of interest in single cells is attractive in cell biology, molecular biology, and biomedicine fields. Time-of-flight-secondary ion mass spectrometry (ToF-SIMS) is a powerful tool for imaging small organic molecules in single cells, yet difficult to image biomacromolecules such as proteins and DNA. Herein, a universal strategy is reported to image specific proteins in single cells by ToF-SIMS following genetic incorporation of fluorine-containing unnatural amino acids as a chemical tag into the proteins via a genetic code expansion technique. The method was developed and validated by imaging a green fluorescence protein (GFP) in Escherichia coli (E. coli) and human HeLa cancer cells and then utilized to visualize the characteristic polar distribution of chemotaxis protein CheA in E. coli cells and the interaction between high-mobility group box 1 protein and cisplatin-damaged DNA in HeLa cells. The present work highlights the power of ToF-SIMS imaging combined with genetically encoded chemical tags for in situ visualization of specific proteins as well as the interactions between proteins and drugs or drug-damaged DNA in single cells.

Proteomic Strategy for Identification of Proteins Responding to Cisplatin-Damaged DNA.

A new proteomic strategy combining functionalized magnetic nanoparticle affinity probes with mass spectrometry was developed to capture and identify proteins specifically responding to 1,2-d(GpG) intrastrand cisplatin-cross-linked DNA, the major DNA lesion caused by cisplatin and thought to induce apoptosis. A 16-mer oligodeoxynucleotide (ODN) duplex and its cisplatin-cross-linked adduct were immobilized on magnetic nanoparticles via click reaction, respectively, to fabricate negative and positive affinity probes which were very stable in cellular protein extracts due to the excellent bio-orthogonality of click chemistry and the inertness of covalent triazole linker. Quantitative mass spectrometry results unambiguously revealed the predominant binding of HMGB1 and HMGB2, the well-established specific binders of 1,2-cisplatin-cross-linked DNA, to the cisplatin-cross-linked ODN, thus validating the accuracy and reliability of our strategy. Furthermore, 5 RNA or single-stranded DNA binding proteins, namely, hnRNP A/B, RRP44, RL30, RL13, and NCL, were demonstrated to recognize specifically the cisplatinated ODN, indicating the significantly unwound ODN duplex by cisplatin cross-linking. In contrast, the binding of a transcription factor TFIIFa to DNA was retarded due to cisplatin damage, implying that the cisplatin lesion stalls DNA transcription. These findings promote understanding in the cellular responses to cisplatin-damaged DNA and inspire further precise elucidation of the action mechanism of cisplatin.

Advances in Toxicological Research of the Anticancer Drug Cisplatin.

Cisplatin is one of the most widely used chemotherapeutic agents for various solid tumors in the clinic due to its high efficacy and broad spectrum. The antineoplastic activity of cisplatin is mainly due to its ability to cross-link with DNA, thus blocking transcription and replication. Unfortunately, the clinical use of cisplatin is limited by its severe, dose-dependent toxic side effects. There are approximately 40 specific toxicities of cisplatin, among which nephrotoxicity is the most common one. Other common side effects include ototoxicity, neurotoxicity, gastrointestinal toxicity, hematological toxicity, cardiotoxicity, and hepatotoxicity. These side effects together reduce the life quality of patients and require lowering the dosage of the drug, even stopping administration, thus weakening the treatment effect. Few effective measures exist clinically against these side effects because the exact mechanisms of various side effects from cisplatin remain still unclear. Therefore, substantial effort has been made to explore the complicated biochemical processes involved in the toxicology of cisplatin, aiming to identify effective ways to reduce or eradicate its toxicity. This review summarizes and reviews the updated advances in the toxicological research of cisplatin. We anticipate to provide insights into the understanding of the mechanisms underlying the side effects of cisplatin and designing comprehensive therapeutic strategies involving cisplatin.

Discovery of Cisplatin Binding to Thymine and Cytosine on a Single-Stranded Oligodeoxynucleotide by High Resolution FT-ICR Mass Spectrometry.

The clinically widely-used anticancer drug, cisplatin, binds strongly to DNA as a DNA-damaging agent. Herein, we investigated the interaction of cisplatin with a 15-mer single-stranded C,T-rich oligodeoxynucleotide, 5'-CCTT4CTT7G8C9T10TCTCC-3' (ODN15), using ultra-high resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) in conjunction with tandem mass spectrometry (top-down MS). Top-down MS analysis with collision-induced dissociation (CID) fragmentation of the mono-platinated and di-platinated ODN15 provided abundant and informative Pt-containing or Pt-free a/[a - B], w and internal fragments, allowing the unambiguous identification of T4, T7, C9, and T10 as the platination sites on the cisplatin-ODN15 adducts. These results revealed that, in addition to the well-established guanine site, the unexpected thermodynamic binding of cisplatin to cytosine and thymine bases was also evident at the oligonucleotide level. Furthermore, the binding models of cisplatin with cytosine and thymine bases were built as the Pt coordinated to cytosine-N(3) and thymine-N(3) with displacement of the proton or tautomerization of thymine. These findings contribute to a better understanding of the mechanism of action of cisplatin and its preference for gene loci when the drug binds to cellular DNA, and also demonstrate the great potential and superiority of FT-ICR MS in studying the interactions of metallodrugs with large biomolecules.

Visualization of metallodrugs in single cells by secondary ion mass spectrometry imaging.

Secondary ion mass spectrometry, including nanoscale secondary ion mass spectrometry (NanoSIMS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS), has emerged as a powerful tool for biological imaging, especially for single cell imaging. SIMS imaging can provide information on subcellular distribution of endogenous and exogenous chemicals, including metallodrugs, from membrane through to cytoplasm and nucleus without labeling, and with high spatial resolution and chemical specificity. In this mini-review, we summarize recent progress in the field of SIMS imaging, particularly in the characterization of the subcellular distribution of metallodrugs. We anticipate that the SIMS imaging method will be widely applied to visualize subcellular distributions of drugs and drug candidates in single cells, exerting significant influence on early drug evaluation and metabolism in medicinal and pharmaceutical chemistry. Recent progress of SIMS applications in characterizing the subcellular distributions of metallodrugs was summarized.

AFM study on the adsorption of Hg2+ on natural molybdenum disulfide in aqueous solutions.

The adsorption of Hg2+ on natural molybdenum disulfide has been studied using atomic force microscope (AFM). The AFM imaging clearly illustrated the adsorption of Hg2+ on the surface of molybdenum disulfide, and also hydration layers on the surfaces. It was found that the presence of a hydration layer on molybdenum disulfide surfaces hindered the Hg2+ adsorption. Also, it was observed that the Hg2+ adsorbed appeared in the form of multilayers. The first adsorbed Hg2+ layer might be mainly attributed to the complexation of Hg2+ with S atoms exposed on molybdenum disulfide surfaces, while the second one might be due to the electrostatic interaction between negatively charged molybdenum disulfide and the cation Hg2+.

Synthesis and applications of sulfopropyl ether γ-cyclodextrin polymer as chiral selector in capillary electrophoresis.

A novel sulfopropyl ether γ-cyclodextrin polymer (SPE-γ-CDP) through polycondensating sulfated cyclodextrins (SCDs) was synthesized. This synthesis approach also has the potential of preparing other derived cyclodextrins (CDs) polymers. The polymerized SCDs took on both the properties of SCDs and certain characteristics of polymers, such as chiral selectivity and high viscosity. Synthesis parameters, including reactions sequence, sulfation, and polycondensation conditions were investigated systematically. The product was characterized by elemental analysis, infrared spectroscopy (IR), and indirect UV detections prior to use as background electrolytes additive. The separation conditions, including the concentration of SPE-γ-CDP, the concentration and pH of running buffer, separation voltage, as well as the additional organic solution were optimized during chiral separation of neutral, acidic, and basic enantiomers in capillary electrophoresis (CE). SPE-γ-CDP was proven to be an effective chiral resolving agent in CE with the advantages of simple synthesis process, low cost, similar ratio of charge-to-mass, low current, great reproducibility, and reusability. Graphical Abstract Synthesis and applications of sulfopropyl ether γ-cyclodextrin polymer.

Effects of quercetin on pharmacokinetics of cefprozil in Chinese-Han male volunteers.

1. The primary objective of this study was to evaluate the effects of quercetin on the pharmacokinetics of cefprozil. The secondary objective was to evaluate the safety of the combined use of cefprozil and quercetin. 2. An open-label, two-period, crossover phase I trial among 24 Han Chinese male subjects was conducted. Participants were given 500 mg of quercetin orally once daily for 15 d followed by single dose of cefprozil (500 mg) on day 15. Serum concentrations of cefprozil were then measured in all participants on day 15. A 15-d washout period was then assigned after which a 500 mg dose of cefprozil was administered and measured in the serum on day 36. 3. All subjects completed the trial, and no serious adverse events were reported. We measured mean serum concentrations of cefprozil in the presence and absence of quercetin in all participants. The maximum serum concentration of cefprozil in the presence of quercetin was 8.18 ug/ml (95% CI: 7.55-8.81) versus a maximum cefprozil concentration of 8.35 ug/ml (95% CI: 7.51-9.19) in the absence of quercetin. We conclude that the concurrent use of quercetin has no substantial effect on serum concentrations of orally administered cefprozil. 4. Co-administration of quercetin showed no statistically significant effects on the pharmacokinetics of cefprozil in healthy Chinese subjects.

Connecting carbon nanotubes to polyoxometalate clusters for engineering high-performance anode materials.

Carbon nanotubes (CNTs) possess excellent structural and electronic properties and have been widely investigated as anode materials. Polyoxometalates (POMs) exhibit superior physical properties such as electronic versatility, redox characteristics and unique molecular structures. In this paper, we report the covalent modification of carbon nanotubes (CNTs) with organosilica-containing polyoxometalate (POM) of [Bu4N]4[SiW11O39{O(SiCH2CH2CH2NH2·HCl)2}] (SiW11-NH2) that leads to the formation of the nanocomposite material of CNTs-SiW11, which has been characterized by FT-IR, XRD, HR-TEM, XPS and Raman spectrum, etc. At a current density of 0.5 mA cm(-2), the application of CNTs-SiW11 nanocomposite as anode material in lithium batteries exhibits the first discharge capacity of 1189 mA h g(-1), and the second discharge capacity of 650 mA h g(-1), which remains stable up to 100 cycles. The CNTs-SiW11 nanocomposite exhibits high discharge capacity, good capacity retention and cycling stability.

Design strategies and biological applications of ß-galactosidase fluorescent sensor in ovarian cancer research and beyond.

Beta-galactosidase (ß-galactosidase), a lysosomal hydrolytic enzyme, plays a critical role in the catalytic hydrolysis of glycosidic bonds, leading to the conversion of lactose into galactose. This hydrolytic enzyme is used as a biomarker in various applications, including enzyme-linked immunosorbent assays (ELISAs), gene expression studies, tuberculosis classification, and in situ hybridization. ß-Galactosidase abnormalities are linked to various diseases, such as ganglioside deposition, primary ovarian cancer, and cell senescence. Thus, effective detection of ß-galactosidase activity may aid disease diagnoses and treatment. Activatable optical probes with high sensitivity, specificity, and spatiotemporal resolution imaging capabilities have become powerful tools for visualization and real time tracking in vivo in the past decade. This manuscript reviews the sensing mechanism, molecular design strategies, and advances of fluorescence probes in the biological application of ß-galactosidase, particularly in the field of ovarian cancer research. Current challenges in tracking ß-galactosidase and future directions are also discussed.