Nur77 increases mitophagy and decreases aggregation of α-synuclein by modulating the p-c-Abl/p-PHB2 Y121 in α-synuclein PFF SH-SY5Y cells and mice.

Parkinson's disease (PD) is characterized by the progressive death of dopamine (DA) neurons and the pathological accumulation of α-synuclein (α-syn) fibrils. In our previous study, simulated PHB2 phosphorylation was utilized to clarify the regulatory role of c-Abl in PHB2-mediated mitophagy in PD models. In this investigation, we employed an independently patented PHB2Y121 phosphorylated antibody in the PD model to further verify that the c-Abl inhibitor STI571 can impede PHB2Y121 phosphorylation, decrease the formation of α-Syn polymers, and improve autophagic levels. The specific involvement of Nur77 in PD pathology has remained elusive. We also investigate the contribution of Nur77, a nuclear transcription factor, to α-syn and mitophagy in PD. Our findings demonstrate that under α-syn, Nur77 translocates from the cytoplasm to the mitochondria, improving PHB-mediated mitophagy by regulating c-Abl phosphorylation. Moreover, Nur77 overexpression alleviates the expression level of pS129-α-syn and the loss of DA neurons in α-syn PFF mice, potentially associated with the p-c-Abl/p-PHB2 Y121 axis. This study provides initial in vivo and in vitro evidence that Nur77 protects PD DA neurons by modulating the p-c-Abl/p-PHB2 Y121 axis, and STI571 holds promise as a treatment for PD.

Depressive symptoms increase the risk of falls and injurious falls in Chinese adults aged ≥ 45 years: A 3-year cohort study.

Background: Falls and depressive symptoms are both public health concerns in China, but the effects of depressive symptoms on falls and injurious falls have not been thoroughly investigated. Methods: This population-based prospective cohort study used data derived from adults aged ≥45 years acquired from the 2015 and 2018 China Health and Retirement Longitudinal Study. Data were analyzed from August 2021 to December 2021. Self-reported depressive symptoms were determined using a 10-item Center for Epidemiologic Studies Depression scale (CESD-10) with a total score range of 0-30. Item responses of 3-4 or 5-7 days were deemed indicative of specific depressive symptoms. The outcome variables were self-reported accidental falls and injurious falls. Results: Of the 12,392 participants included in the study, 3,671 (29.6%) had high baseline depressive symptoms (CESD-10 scores ≥ 10), 1,892 (15.3%) experienced falls, and 805 (6.5%) experienced injurious falls during 2015-2018 follow-up. High depressive symptoms increased the risk of falls [odds ratio (OR) 1.34, 95% confidence interval (CI) 1.19-1.50] and injurious falls (OR 1.28, 95% CI 1.09-1.51) in a multivariable logistic regression model adjusted for major demographic, health-related, and anthropometric covariates. All of the 10 specific depressive symptoms except "felt hopeless" were associated with falls, and four specific symptoms significantly increased the risk of injurious falls; "had trouble concentrating" (OR 1.32, 95% CI 1.13-1.55); "felt depressed" (OR 1.32, 95% CI 1.12-1.55); "everything was an effort" (OR 1.23, 95% CI 1.04-1.45); and "restless sleep" (OR 1.18, 95% CI 1.02-1.40). Conclusion: High depressive symptoms are significantly related to risk of falls and injurious falls. Four specific symptoms (had trouble concentrating, felt depressed, everything was an effort, and restless sleep) increase the risk of injurious falls in Chinese adults aged ≥ 45 years.

A Multiscale Clustering Approach for Non-IID Nominal Data.

Multiscale brings great benefits for people to observe objects or problems from different perspectives. Multiscale clustering has been widely studied in various disciplines. However, most of the research studies are only for the numerical dataset, which is a lack of research on the clustering of nominal dataset, especially the data are nonindependent and identically distributed (Non-IID). Aiming at the current research situation, this paper proposes a multiscale clustering framework based on Non-IID nominal data. Firstly, the benchmark-scale dataset is clustered based on coupled metric similarity measure. Secondly, it is proposed to transform the clustering results from benchmark scale to target scale that the two algorithms are named upscaling based on single chain and downscaling based on Lanczos kernel, respectively. Finally, experiments are performed using five public datasets and one real dataset of the Hebei province of China. The results showed that the method can provide us not only competitive performance but also reduce computational cost.

Identification Of Putative Gene Signatures Associated With Diagnosis And Prognosis Of Breast Cancer.

Purpose: This study aimed to identify potential diagnostic and therapeutic biomakers for the development of breast cancer (BC). Methods: GSE86374 dataset containing 159 samples was acquired from the Gene Expression Omnibus (GEO) database followed by differentially expressed genes (DEGs) identification and cluster analysis. Corresponding functional enrichment and protein-protein interaction (PPI) network analyses were performed to identify hub genes. Prognostic evaluation using clinical information obtained from TCGA database and hub genes was conducted to screen for crucial indicators for BC progression. The risk model was established and validated. Results: In total, 186 DEGs were identified and grouped into four clusters: 96 in cluster 1; 69 in cluster 2; 16 in cluster 3; and 5 in cluster 4. Functional enrichment analysis showed that DEGs, including ADH1B in cluster 1, were dramatically enriched in the tyrosine and drug metabolism pathways, while genes in cluster 2, including SPP1 and RRM2, played crucial roles in PI3K-Akt and p53 signalling pathway. SPP1 and RRM2 served as hub genes in the PPI network, resulting in an support vector machine classifier with good accuracy and specificity.Ad ditionally, the results of prognostic analysis suggest that age, metastasis stage, SPP1 and ADH1B were correlated with risk of BC, which was validated by using the established risk model analysis. Conclusion: SPP1, RRM2 and ADH1B appear to play vital roles in the development of BC. Age and TNM stage were also preferentially associated with risk of developing BC. Evaluation of the risk model based on larger sample size and further experimental validation are required.

Thermodynamics Controlled Sharp Transformation from InP to GaP Nanowires via Introducing Trace Amount of Gallium.

Growth of high-quality III-V nanowires at a low cost for optoelectronic and electronic applications is a long-term pursuit of research. Still, controlled synthesis of III-V nanowires using chemical vapor deposition method is challenge and lack theory guidance. Here, we show the growth of InP and GaP nanowires in a large area with a high density using a vacuum chemical vapor deposition method. It is revealed that high growth temperature is required to avoid oxide formation and increase the crystal purity of InP nanowires. Introduction of a small amount of Ga into the reactor leads to the formation of GaP nanowires instead of ternary InGaP nanowires. Thermodynamic calculation within the calculation of phase diagrams (CALPHAD) approach is applied to explain this novel growth phenomenon. Composition and driving force calculations of the solidification process demonstrate that only 1 at.% of Ga in the catalyst is enough to tune the nanowire formation from InP to GaP, since GaP nucleation shows a much larger driving force. The combined thermodynamic studies together with III-V nanowire growth studies provide an excellent example to guide the nanowire growth.

Facet-dependent growth of InAsP quantum wells in InP nanowire and nanomembrane arrays.

Selective area epitaxy is a powerful growth technique that has been used to produce III-V semiconductor nanowire and nanomembrane arrays for photonic and electronic applications. The incorporation of a heterostructure such as quantum wells (QWs) brings new functionality and further broadens their applications. Using InP nanowires and nanomembranes as templates, we investigate the growth of InAsP QWs on these pure wurtzite nanostructures. InAsP QWs grow both axially and laterally on the nanowires and nanomembranes, forming a zinc blende phase axially and wurtzite phase on the sidewalls. On the non-polar {11[combining macron]00} sidewalls, the radial QW selectively grows on one sidewall which is located at the semi-polar 〈112[combining macron]〉 A side of the axial QW, causing the shape evolution of the nanowires from hexagonal to triangular cross section. For nanomembranes with {11[combining macron]00} sidewalls, the radial QW grows asymmetrically on the {11[combining macron]00} facet, destroying their symmetry. In comparison, nanomembranes with {112[combining macron]0} sidewalls are shown to be an ideal template for the growth of InAsP QWs, thanks to the uniform QW formation. These QWs emit strongly in the near IR region at room temperature and their emission can be tuned by changing their thickness or composition. These findings enrich our understanding of the QW growth, which provides new insights for heterostructure design in other III-V nanostructures.

Preparation and mechanism of hydroxyapatite hollow microspheres with different surface charge by biomimetic method.

To meet the different application requirements in various fields, hydroxyapatite (HA) hollow microspheres with different surface charge were synthesized successfully by biomimetic method using Ca(NO3)2·4H2O and (NH4)2HPO4 in the presence of polyethylene glycol (PEG). Scanning electron microscopy (SEM), High-resolution TEM (HRTEM), X-ray powder diffraction (XRD), and Zeta PALS were used to characterize the obtained samples. The results indicated that the concentration of PEG and temperature significantly affect the morphology of the obtained samples. After incubation for 5 d, the HA hollow microspheres with positive surface charge, HA spherical nanoparticles with surface charge close to zero and calcium deficiency HA (d-HA) hollow microspheres with negative surface charge were obtained respectively in the presence of 5% PEG, 6% PEG and 7% PEG at 15 °C. Brunauer-Emmett-Teller (BET) revealed that the specific surface area of HA hollow microspheres reached 98.50 m2/g, while that of HA spherical nanoparticles were only 4.12 m2/g, hollow microspheres show a better application prospect. The possible formation mechanism was also discussed. Ca/P molar ratio >1.67, the surface charge of HA hollow microspheres inclines to be positive. Ca/P molar ratio <1.67, the surface charge of d-HA hollow microspheres tends to be negative.

Effects of copper salts on performance, antibiotic resistance genes, and microbial community during thermophilic anaerobic digestion of swine manure.

This study investigated methane production and ARGs reduction during thermophilic AD of swine manure with the addition of different Cu salts (cupric sulfate, cupric glycinate, and the 1:1 mixture of these two salts). Results showed methane production was increased by 28.78% through adding mixed Cu salts. The mixed Cu group effectively reduced total ARGs abundance by 26.94%, suggesting mixed Cu salts did not promote the potential ARGs risk. The positive effects of mixed Cu salts on AD performance and ARGs removal might be ascribed to the low bioavailability. Microbial community analysis indicated the highest abundances of Clostridia_MBA03 and Methanobacterium in the mixed Cu group might cause the increased methane production. Spearman's rank correlation analysis elucidated the succession in microbial community induced by environmental factors was the main driver for shaping ARGs profiles. Thus, mixed Cu salts could be an alternative to replace the inorganic Cu salt in animal feed additives.

Potential anticancer agent for selective damage to mitochondria or lysosomes: Naphthalimide-modified fluorescent biomarker half-sandwich iridium (III) and ruthenium (II) complexes.

In this work, five naphthalimide-modified half-sandwich iridium and ruthenium complexes ([(η5-Cpx)Ir(NˆN)Cl]PF6, [(η6-p-cym)Ru(NˆN)Cl]PF6) have been presented. The anticancer activities of the complexes against various cancer cell lines were investigated, among them, complexes 2 and 4 showed better anticancer activity than cisplatin, and their anticancer activity is better than complex 5 without fluorophore. In addition, a series of biological tests of complex 2 were performed using flow cytometry, the results indicated that the complex could induce cell death in a variety of ways. By changing of the ligands, the complexes exhibited different photophysical properties, and the mechanism of action of the complexes entering the cell and inducing apoptosis are different. Moreover, complex 2 successfully targeted mitochondria, while complex 4 targeted lysosomes, causing mitochondrial damage and lysosomal damage to induce apoptosis. Excitingly, complex 2 has good antimetastatic ability to cancer cells. Furthermore, complexes 2 and 4 did not have a significant effect on the NADH binding reaction, but they had a moderate binding ability to BSA.

Serendipitous Synthesis of Five-Coordinated Half-Sandwich Aminoimine Iridium(III) and Ruthenium(II) Complexes and Their Application as Potent Anticancer Agents.

Stable five-coordinated (16-electron) half-sandwich iridium(III) and ruthenium(II) complexes are rarely reported, and their biological evaluations have not been considered to date. Herein, in an experiment designed to synthesize six-coordinated half-sandwich iridium(III) and ruthenium(II) complexes containing N,N-chelated α-keto-ß-diimine ligands, we observed the serendipitous formation of half-sandwich aminoimine iridium(III) and ruthenium(II) complexes via solvent-involved rearrangement reaction. These unsaturated 16-electron complexes had sufficient stability in DMSO-water solution. Moreover, no reaction with two-electron donors (CO and PPh3) and nucleobase (9-MeA and 9-EtG) was observed. Most of the complexes show good anticancer activities toward A549, HeLa, and HepG2 cancer cells, which are higher than the clinical drug cisplatin. The investigation of mechanism by flow cytometry showed that the complexes exert their anticancer efficacy by inducing apoptosis or necrosis, and increasing the intracellular ROS level. In addition, fluorescence property of these complexes makes it possible to investigate the microscopic mechanism by confocal microscopy. Notably, the complexes Ir3 and Ru1 enter A549 cancer cells through an energy-independent pathway, and they are mainly located in mitochondria and lysosomes.

Rhodamine-modified fluorescent half-sandwich iridium and ruthenium complexes: potential application as bioimaging and anticancer agents.

Most half-sandwich metal anticancer complexes are non-fluorescent, which results in an uncertain mechanism of action (MoA). We designed and synthesized eight fluorescent half-sandwich iridium (Ir) and ruthenium (Ru) complexes by introducing rhodamine derivatives into the N^N-chelating ligand. These complexes have features of bio-imaging and anticancer agents and may merit future development as novel anticancer agents.

Zwitterionic and cationic half-sandwich iridium(iii) ruthenium(ii) complexes bearing sulfonate groups: synthesis, characterization and their different biological activities.

Previous studies on the neutral and cationic half-sandwich iridium(iii) and ruthenium(ii) complexes showed that the charge and the substitution pattern of the bidentate ligands, as well as the nature of the accompanying counteranion have a significant effect on their biological activities. In this contribution, a series of zwitterionic and cationic half-sandwich iridium(iii) and ruthenium(ii) complexes containing sulfonate groups have been prepared and characterized. The different locations of counteranions between these two kinds of complexes exert great influence on the cytotoxic activity towards cancer cells. The various possible mechanism of actions (MoAs) of the complexes were determined by flow cytometry. This work has shown for the first time the different biological activities between zwitterionic and cationic half-sandwich complexes.

Design, synthesis, and evaluation of fluorine and Naphthyridine-Based half-sandwich organoiridium/ruthenium complexes with bioimaging and anticancer activity.

A range of fluorine and naphthyridine-based half-sandwich iridium (III) and ruthenium (II) complexes were synthesized. The iridium complexes possessed excellent antiproliferative properties, a substantial improvement over cisplatin, especially the best 1C containing the fluorine atom and 2C containing the naphthyridine. On the contrary, the ruthenium complexes displayed much less antiproliferative activity. Two X-ray crystal structures were determined. The cytotoxicity of the complexes can be changed flexible by regulating the metal center and the ancillary ligands. The best complex 1C was chose to study further on the mechanism of action. The chemical reactivity such as hydrolysis, reaction with nucleobases, glutathione and catalytic conversion of NADH to NAD+, were investigated. Complex 1C can react with 9-ethylguanine (9-EtG) and catalyze oxidation of NADH. In addition, the self-luminescence of the complex 1C was also successfully used in confocal microscopy images for elucidating the subcellular localization. Complex 1C specifically targeted to lysosomes in A549 cancer cells and caused lysosomal damages and promote cathepsin B released. Flow cytometry studies confirmed that the biological effects of this type of complexes induced apoptosis, especially late apoptosis. Our results suggested that changes in the mitochondria membrane potential were responsible for apoptosis. The chemistry and biological studies has showed that this class of metal complexes are worthy of further exploration for the design of novel anticancer drugs.

Half-Sandwich Iridium and Ruthenium Complexes: Effective Tracking in Cells and Anticancer Studies.

Half-sandwich metal-based anticancer complexes suffer from uncertain targets and mechanisms of action. Herein we report the observation of the images of half-sandwich iridium and ruthenium complexes in cells detected by confocal microscopy. The confocal microscopy images showed that the cyclopentadienyl iridium complex 1 mainly accumulated in nuclei in A549 lung cancer cells, whereas the arene ruthenium complex 3 is located in mitochondria and lysosomes, mostly in mitochondria, although both complexes entered A549 cells mainly through energy-dependent active transport. The nuclear morphological changes caused by Ir complex 1 were also detected by confocal microscopy. Ir complex 1 is more potent than cisplatin toward A549 and HeLa cells. DNA binding studies involved interaction with the nucleobases 9-ethylguanine, 9-methyladenine, ctDNA, and plasmid DNA. The determination of bovine serum albumin binding was also performed. Hydrolysis, stability, nucleobase binding, and catalytic NAD+/NADH hydride transfer tests for complexes 1 and 3 were also carried out. Both complexes activated depolarization of mitochondrial membrane potential and intracellular ROS overproduction and induced cell apoptosis. Complex 3 arrested the cell cycle at the G0/G1 phase by inactivation of CDK 4/cyclin D1. This work paves the way to track and monitor half-sandwich metal complexes in cells, shines a light on understanding their mechanism of action, and indicates their potential application as theranostic agents.

Half-sandwich Iridium(III) Benzimidazole-Appended Imidazolium-Based N-heterocyclic Carbene Complexes and Antitumor Application.

A series of half-sandwich iridium(III) benzimidazole-appended imidazolium-based N-heterocyclic carbene (NHC) antitumor complexes [(η5 -Cpx )Ir(C^N)Cl]Cl, where Cpx is pentamethylcyclopentadienyl (Cp*) or its biphenyl derivative (Cpxbiph ) and C^N is a NHC chelating ligand, were successfully synthesized and characterized. The IrIII complexes showed potential antitumor activity against A549 cells, at most three times more potent than cis-platin under the same conditions. Complexes could bind to BSA by a static quenching mode, catalyzing the change of NADH to NAD+ and inducing the production of reactive oxygen species (maximum turnover number, 9.8), which play an important role in regulating cell apoptosis. Confocal microscopy showed that the complexes could specifically target lysosomes in cells with a Pearson's co-localization coefficient 0.76 and 0.72 after 1 h and 6 h, respectively, followed an energy-dependent cellular uptake mechanism and damaged the integrity of lysosomes. At the same time, complexes caused a marked loss of mitochondrial membrane potential.

Half-sandwich IridiumIIIN-heterocyclic carbene antitumor complexes and biological applications.

Series of half-sandwich IrIIIN-heterocyclic carbene (NHC) antitumor complexes [(η5-Cp*)Ir(C^C)Cl] have been synthesized and characterized (Cp* is pentamethyl cyclopentadienyl, and C^C are four NHC chelating ligands containing phenyl rings at different positions). IrIII complexes showed potent antitumor activity with IC50 values ranged from 3.9 to 11.8 µM against A549 cells by the MTT assay. Complexes can catalyze the conversion of the coenzyme NADH to NAD+ and induce the production of reactive oxygen species (ROS), and bonding to BSA by static quenching mode. Complexes can arrest the cell cycle in G1 or S phase and reduce the mitochondrial membrane potential. Confocal microscopy test show complexes could target the lysosome and mitochondria in cells with the Pearson's colocalization coefficient of 0.82 and 0.21 after 12 h, respectively, and followed by an energy-dependent cellular uptake mechanism.

Highly potent half-sandwich iridium and ruthenium complexes as lysosome-targeted imaging and anticancer agents.

In this study, six half-sandwich luminescent iridium (Ir) and ruthenium (Ru) anticancer complexes bearing P^P-chelating ligands 1,2-bis(diphenylphosphino)benzene (dppbz) and 1,8-bis(diphenylphosphino)naphthalene (dppn) were synthesized and characterized via1H-NMR spectroscopy, 31P-NMR spectroscopy, mass spectrometry, elemental analysis and X-ray crystallography. All the complexes displayed more potent anticancer activity than cisplatin towards A549 lung cancer cells and HeLa cervical cancer cells, especially the most potent iridium complex Ir3, which was 73 times more potent than cisplatin against A549 cells. Different from cisplatin, no nucleobase adducts of Ir3 were detected. With the help of the self-luminescence of complex Ir3 and confocal microscopy, it was observed that Ir3 efficiently penetrated into the A549 cells via energy-dependent active transport, and specifically accumulated in lysosomes, affected the permeabilization of the lysosomal membranes and induced caspase-dependent cell death through lysosomal damage. Both apoptosis and autophagy of the A549 cells were observed. The reactive oxygen species (ROS) elevation, reduction of the mitochondrial membrane potential and cell cycle arrest at the G0/G1 phase also contributed to the observed cytotoxicity of Ir3. We demonstrate that these half-sandwich Ir and Ru anticancer complexes have different anticancer mechanism of action from that of cisplatin, which can be developed as potential multifunctional theranostic platforms that combine bioimaging and anticancer capabilities.

Phenoxide chelated Ir(iii) N-heterocyclic carbene complexes: synthesis, characterization, and evaluation of their in vitro anticancer activity.

Twelve novel half-sandwich IrIII-NHC complexes [(η5-Cpx)Ir(C^O)Cl] were synthesized and characterized. These complexes showed higher cytotoxic activity toward A549 cells and HeLa cells than cisplatin. An increase in the number of contained phenyl groups was related to better anticancer activity. The reaction of complexes with nucleobases 9-MeA, nucleobases 9-EtG, plasmid DNA and CT-DNA showed no significant effects. These complexes captured hydrogen from NADH and converted it to NAD+, which produced the reactive oxygen species (ROS). ROS led to a decrease in the mitochondrial membrane potential and lysosomal damage, finally inducing apoptosis.

Imine-N-Heterocyclic Carbenes as Versatile Ligands in Ruthenium(II) p-Cymene Anticancer Complexes: A Structure-Activity Relationship Study.

A family of novel imine-N-heterocyclic carbene ruthenium(II) complexes of the general formula [(η6 -p-cymene)Ru(C^N)Cl]PF6 - (where C^N is an imine-N-heterocyclic carbene chelating ligand with varying substituents) have been prepared and characterized. In this imine-N-heterocyclic carbene chelating ligand framework, there are three potential sites that can be modified, which distinguishes this class of ligand and provides a body of flexibilities and opportunities to tune the cytotoxicity of these ruthenium(II) complexes. The influence of substituent effects of three tunable domains on the anticancer activity and catalytic ability in converting coenzyme NADH to NAD+ is investigated. This family of complexes displays an exceedingly distinct anticancer activity against A549 cancer cells, despite their close structural similarity. Complex 9 shows the highest anticancer activity in this series against A549 cancer cells (IC50 =14.36 µm), with an approximately 1.5-fold better activity than the clinical platinum drug cisplatin (IC50 =21.30 µm) in A549 cancer cells. Mechanistic studies reveal that complex 9 mediates cell death mainly through cell stress, including cell cycle arrest, inducing apoptosis, increasing intracellular reactive oxygen species (ROS) levels, and depolarization of the mitochondrial membrane potential (MMP). Furthermore, lysosomal damage is also detected by confocal microscopy.

Lysosome-Targeted Chemotherapeutics: Half-Sandwich Ruthenium(II) Complexes That Are Selectively Toxic to Cancer Cells.

Poor selectivity between cancer cells and normal cells is one of the major limitations of cancer chemotherapy. Lysosome-targeted ruthenium-based complexes target tumor cells selectively, only displaying rather weak cytotoxicity or inactivity toward normal cells. Confocal microscopy was employed for the first time to determine the cellular localization of the half-sandwich Ru complex.