Bioelectrocatalytic Activity of One-Dimensional Porous Pt Nanoribbons for Efficient Inhibition of Tumor Growth and Metastasis.

Designing and synthesizing one-dimensional porous Pt nanocrystals with unique optical, electrocatalytic, and theranostic properties are gaining lots of attention, especially to overcome the challenges of tumor recurrence and resistance to platinum-based chemotherapy. Herein, we represented an interesting report of a one-step and facile strategy for synthesizing multifunctional one-dimensional (1D) porous Pt nanoribbons (PtNRBs) with highly efficient therapeutic effects on cancer cells based on inherent electrocatalytic activity. The critical point in the formation of luminescent porous PtNRBs was the use of human hemoglobin (Hb) as a shape-regulating, stabilizing, and reducing agent with facet-specific domains on which fluorescent platinum nanoclusters at first are aggregated by aggregation-induced emission phenomena (AIE) and then crystallized into contact and penetration twins, as intermediate products, followed by shaping of the final luminescent porous ribbon nanomaterials, owing to oriented attachment association via the Ostwald ripening mechanism. From a medical point of view, the key strategy for effective cancer therapy occured via using low-dosage ethanol in the presence of electroactive porous PtNRBs based on intracellular ethanol oxidation-mediated reactive oxygen species (ROS) generation. The role of heme groups of Hb, as electrocatalytically active centers, was successfully demonstrated in both kinetically controlled anisotropic growth of NRBs for slowing down the reduction of Pt(II) followed by oligomerization of Pt(II)-Hb complexes via platinophilic interactions as well as electrocatalytic ethanol oxidation for therapy. Interestingly, hyaluronic acid-targeted (HA) Hb-PtNRB in the presence of low-dose ethanol caused extraordinary arrest of tumor growth and metastasis with no recurrence even after the treatment course stopped, which caused elongation of tumor-bearing mice survival. HA/Hb-PtNRB was completely biocompatible and exhibited high tumor-targeting efficacy for fluorescent imaging of breast tumors. Therefore, the synergistic electrocatalytic activity of PtNRBs is presented as an efficient and safe cancer theranostic method for the first time.

Quantitative Profiling Method for Oxylipins in Neurodegenerative Diseases by Liquid Chromatography Coupled with Tandem Mass Spectrometry.

Aging is one of the major risk factors for many chronic diseases, including diabetes, neuropathy, hypertension, cancer, and neurodegenerative diseases. However, the mechanism behind aging and how aging affects a variety of disease progression remains unknown. Recent research demonstrated the cytochrome P450 (CYP)-epoxide hydrolase (EH) metabolites of polyunsaturated fatty acids (PUFAs) play a critical role in the abovementioned age-associated diseases. Therefore, aging could affect the abovementioned chronic diseases by modulating CYP-EH PUFA metabolism. Unfortunately, investigating how aging affects CYP-EH metabolism in human and mammalian models poses significant challenges. In this regard, we will use C. elegans as a model organism to investigate the aging effects on CYP-EH metabolism of PUFA, owing to its long history of being used to study aging and its associated benefits of conducting aging research. This project will develop analytical tools to measure the endogenous levels of CYP-EH PUFA metabolites in C. elegans using state-of-the-art ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). These metabolites are very potent but present in low abundance. The dramatic increase in sensitivity in UPLC-MS/MS allows us to monitor these metabolites over the lifespan of C. elegans with minimum samples. Our results show that C. elegans produces similar CYP PUFA metabolites to mammals and humans using our SPE-UPLC-MS/MS method. We will also show that our method successfully determined the CYP-EH PUFA metabolites profile changes induced by the inhibition of C. elegans EH. The method developed from this project will significantly improve our understanding of the role of dietary PUFAs and associated metabolism on aging and neurodegeneration and will uncover new mechanisms of how aging affects neurodegeneration through the modulation of PUFA metabolic pathways.

Cytochrome P450 and Epoxide Hydrolase Metabolites in Aß and tau-induced Neurodegeneration: Insights from Caenorhabditis elegans.

This study aims to uncover potent cytochrome P450 (CYP) and epoxide hydrolase (EH) metabolites implicated in Aß and/or tau-induced neurodegeneration, independent of neuroinflammation, by utilizing Caenorhabditis elegans (C. elegans) as a model organism. Our research reveals that Aß and/or tau expression in C. elegans disrupts the oxylipin profile, and epoxide hydrolase inhibition alleviates the ensuing neurodegeneration, likely through elevating the epoxy-to-hydroxy ratio of various CYP-EH metabolites. In addition, our results indicated that the Aß and tau likely affect the CYP-EH metabolism of PUFA through different mechanism. These findings emphasize the intriguing relationship between lipid metabolites and neurodegenerations, in particular, those linked to Aß and/or tau aggregation. Furthermore, our investigation sheds light on the crucial and captivating role of CYP PUFA metabolites in C. elegans physiology, opening up possibilities for broader implications in mammalian and human contexts.

Dihydroxy-Metabolites of Dihomo-γ-linolenic Acid Drive Ferroptosis-Mediated Neurodegeneration.

Even after decades of research, the mechanism of neurodegeneration remains understudied, hindering the discovery of effective treatments for neurodegenerative diseases. Recent reports suggest that ferroptosis could be a novel therapeutic target for neurodegenerative diseases. While polyunsaturated fatty acid (PUFA) plays an important role in neurodegeneration and ferroptosis, how PUFAs may trigger these processes remains largely unknown. PUFA metabolites from cytochrome P450 and epoxide hydrolase metabolic pathways may modulate neurodegeneration. Here, we test the hypothesis that specific PUFAs regulate neurodegeneration through the action of their downstream metabolites by affecting ferroptosis. We find that the PUFA dihomo-γ-linolenic acid (DGLA) specifically induces ferroptosis-mediated neurodegeneration in dopaminergic neurons. Using synthetic chemical probes, targeted metabolomics, and genetic mutants, we show that DGLA triggers neurodegeneration upon conversion to dihydroxyeicosadienoic acid through the action of CYP-EH (CYP, cytochrome P450; EH, epoxide hydrolase), representing a new class of lipid metabolites that induce neurodegeneration via ferroptosis.

Dihydroxy-Metabolites of Dihomo-gamma-linolenic Acid Drive Ferroptosis-Mediated Neurodegeneration.

Even after decades of research, the mechanism of neurodegeneration remains understudied, hindering the discovery of effective treatments for neurodegenerative diseases. Recent reports suggest that ferroptosis could be a novel therapeutic target for neurodegenerative diseases. While polyunsaturated fatty acid (PUFA) plays an important role in neurodegeneration and ferroptosis, how PUFAs may trigger these processes remains largely unknown. PUFA metabolites from cytochrome P450 and epoxide hydrolase metabolic pathways may modulate neurodegeneration. Here, we test the hypothesis that specific PUFAs regulate neurodegeneration through the action of their downstream metabolites by affecting ferroptosis. We find that the PUFA, dihomo gamma linolenic acid (DGLA), specifically induces ferroptosis-mediated neurodegeneration in dopaminergic neurons. Using synthetic chemical probes, targeted metabolomics, and genetic mutants, we show that DGLA triggers neurodegeneration upon conversion to dihydroxyeicosadienoic acid through the action of CYP-EH, representing a new class of lipid metabolite that induces neurodegeneration via ferroptosis.

Cytochrome P450 Metabolism of Polyunsaturated Fatty Acids and Neurodegeneration.

Due to the aging population in the world, neurodegenerative diseases have become a serious public health issue that greatly impacts patients' quality of life and adds a huge economic burden. Even after decades of research, there is no effective curative treatment for neurodegenerative diseases. Polyunsaturated fatty acids (PUFAs) have become an emerging dietary medical intervention for health maintenance and treatment of diseases, including neurodegenerative diseases. Recent research demonstrated that the oxidized metabolites, particularly the cytochrome P450 (CYP) metabolites, of PUFAs are beneficial to several neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease; however, their mechanism(s) remains unclear. The endogenous levels of CYP metabolites are greatly affected by our diet, endogenous synthesis, and the downstream metabolism. While the activity of omega-3 (ω-3) CYP PUFA metabolites and omega-6 (ω-6) CYP PUFA metabolites largely overlap, the ω-3 CYP PUFA metabolites are more active in general. In this review, we will briefly summarize recent findings regarding the biosynthesis and metabolism of CYP PUFA metabolites. We will also discuss the potential mechanism(s) of CYP PUFA metabolites in neurodegeneration, which will ultimately improve our understanding of how PUFAs affect neurodegeneration and may identify potential drug targets for neurodegenerative diseases.

Aptamer-Based Fluorescent Biosensing of Adenosine Triphosphate and Cytochrome c via Aggregation-Induced Emission Enhancement on Novel Label-Free DNA-Capped Silver Nanoclusters/Graphene Oxide Nanohybrids.

Four fluorescent DNA-stabilized fluorescent silver nanoclusters (DNA-AgNCs) were designed and synthesized with differences in lengths of cytosine-rich DNA strand (as the stabilizing agent) and target-specific strand DNA aptamers for adenosine triphosphate (ATP) and cytochrome c (Cyt c). After their nanohybrid formation with graphene oxide (GO), it was unexpectedly found that, depending on the composition of the base and length of the strand DNA aptamer, the fluorescence intensity of three of the nanohybrids significantly enhanced. Our experimental observations and quantum mechanical calculations provided an insight into the mechanisms underlying the behavior of DNA-AgNCs/GO nanohybrids. The enhanced fluorescence was found to be attributed to the aggregation-induced emission enhancement (AIE) characteristic of the DNA-AgNCs adsorbed on the GO surface, as confirmed evidently by both fluorescence and transmission electron microscopies. The AIE is a result of hardness and oxidation properties of GO, which lead to enhanced argenophilic interaction and thus to increased Ag(I)-DNA complex shell aggregation. Consequently, two of the DNA-AgNCs/GO nanohybrids were successfully extended to construct highly selective, sensitive, label-free, and simple aptasensors for biosensing of ATP (LOD = 0.42 nM) and Cyt c (LOD = 2.3 nM) in lysed Escherichia coli DH5 α cells and mouse embryonic stem cells, respectively. These fundamental findings are expected to significantly influence the designing and engineering of new AgNCs/GO-based AIE biosensors.

A highly selective semiconducting polymer dots-based "off-on" fluorescent nanoprobe for iron, copper and histidine detection and imaging in living cells.

Semiconducting polymer dots (PDs) hold a great promise as fluorescence nanoprobes, due to their photostability, biocompatibility, and high quantum yield. Herein, the synthesis and characterization of highly fluorescent PDs for selective and sensitive detection of Fe3+,Cu2+, and histidine (His) have been reported. First, carboxyl functionalized poly[(9,9-dioctylfluorenyl-2,7-diyl)-alt-co-(1,4-benzo-(2,1',3)-thiadiazole)] (PFBT) PDs were synthesized through a nano-precipitation technique, and then they were functionalized by -COOH groups using 9-anthracenecarboxylic acid. The formation of PDs was proved using transmission electron microscopy, dynamic light scattering, and Fourier transform infrared (FTIR) spectroscopy analyses. The PDs exhibited a yellow fluorescence with a peak centered at 540 nm (photo-excited at 460 nm) with a quantum yield of 25%. The fluorescence of PDs significantly quenched in the presence of Cu2+ ion, and then selectively recovered upon addition of His, providing the possibility of constructing a sensitive Cu2+-His off-on fluorescent nanoprobe. The PDs exhibited a linear dynamic range for Cu2+ from 0.1 to 630 µmol L-1 with a limit of detection of 61.7 nmol L-1, and for Fe3+ from 0.1 to 720 µmol L-1 with a limit of detection of 58.1 nmol L-1. In addition, the PDs/Cu2+ probe showed a linear dynamic range for His from 0.1 to 920 µmol L-1 with a limit of detection of 79.6 nmol L-1. Besides, the prepared PDs/Cu2+ probe exhibited a promising potential for selective and sensitive sensing of His in blood serum and for intracellular imaging.

Shape-Controlled Synthesis of Luminescent Hemoglobin Capped Hollow Porous Platinum Nanoclusters and their Application to Catalytic Oxygen Reduction and Cancer Imaging.

Engineering hollow and porous platinum nanostructures using biomolecular templates is currently a significant focus for the enhancement of their facet-dependent optical, electronic, and electrocatalytic properties. However, remains a formidable challenge due to lack of appropriate biomolecules to have a structure-function relationship with nanocrystal facet development. Herein, human hemoglobin found to have facet-binding abilities that can control the morphology and optical properties of the platinum nanoclusters (Pt NCs) by regulation of the growth kinetics in alkaline media. Observations revealed the growth of unusual polyhedra by shape-directed nanocluster attachment along a certain orientation accompanied by Ostwald ripening and, in turn, yield well-dispersed hollow single-crystal nanotetrahedrons, which can easily self-aggregated and crystallized into porous and polycrystalline microspheres. The spontaneous, biobased organization of Pt NCs allow the intrinsic aggregation-induced emission (AIE) features in terms of the platinophilic interactions between Pt(II)-Hb complexes on the Pt(0) cores, thereby controlling the degree of aggregation and the luminescent intensity of Pt(0)@Pt(II)-Hb core-shell NCs. The Hb-Pt NCs exhibited high-performance electrocatalytic oxygen reduction providing a fundamental basis for outstanding catalytic enhancement of Hb-Pt catalysts based on morphology dependent and active site concentration for the four-electron reduction of oxygen. The as-prepared Hb-Pt NCs also exhibited high potential to use in cellular labeling and imaging thanks to the excellent photostability, chemical stability, and low cytotoxicity.

Electrochemical aptamer/antibody based sandwich immunosensor for the detection of EGFR, a cancer biomarker, using gold nanoparticles as a signaling probe.

Detection of epidermal growth factor receptor (EGFR) in biological fluids is of paramount importance, since it has significant application in cancer diagnosis, drug development, and therapy monitoring. EGFR is a cancer biomarker, and its overexpression is associated with the development of some types of cancer. Herein, we report on the development of a sensitive and selective electrochemical aptamer/antibody (Apt/Ab) sandwich immunosensor for detection of EGFR. In this study, a biotinylated anti-human EGFR Apt was immobilized on streptavidin-coated magnetic beads (MB) and served as a capture probe. A polyclonal anti-human EGFR Ab was conjugated to citrate-coated gold nanoparticles (AuNPs) and used as a signaling probe. In the presence of EGFR, an Apt-EGFR-Ab sandwich was formed on the MB surface. The extent of the complexation was evaluated by differential pulse voltammetry of AuNPs after their dissolution in HCl. Under optimal conditions, the dynamic concentration range of the immunosensor for EGFR spanned from 1 to 40 ng/mL, with a low detection limit of 50 pg/mL, and RSD percent of less than 4.2%. The proposed approach takes advantage of sandwich assay for high specificity, MBs for fast separation, and electrochemical method for cost-effective and sensitive detection. In this proof-of-principle study, we demonstrate the potential clinical efficacy of the immunosensor for monitoring of chemotherapy effectiveness in breast cancer samples.