Myocardial infarction drives trained immunity of monocytes, accelerating atherosclerosis.

BACKGROUND AND AIMS: Survivors of acute coronary syndromes face an elevated risk of recurrent atherosclerosis-related vascular events despite advanced medical treatments. The underlying causes remain unclear. This study aims to investigate whether myocardial infarction (MI)-induced trained immunity in monocytes could sustain proatherogenic traits and expedite atherosclerosis. METHODS: Apolipoprotein-E deficient (ApoE-/-) mice and adoptive bone marrow transfer chimeric mice underwent MI or myocardial ischaemia-reperfusion (IR). A subsequent 12-week high-fat diet (HFD) regimen was implemented to elucidate the mechanism behind monocyte trained immunity. In addition, classical monocytes were analysed by flow cytometry in the blood of enrolled patients. RESULTS: In MI and IR mice, blood monocytes and bone marrow-derived macrophages exhibited elevated spleen tyrosine kinase (SYK), lysine methyltransferase 5A (KMT5A), and CCHC-type zinc finger nucleic acid-binding protein (CNBP) expression upon exposure to a HFD or oxidized LDL (oxLDL) stimulation. MI-induced trained immunity was transmissible by transplantation of bone marrow to accelerate atherosclerosis in naive recipients. KMT5A specifically recruited monomethylation of Lys20 of histone H4 (H4K20me) to the gene body of SYK and synergistically transactivated SYK with CNBP. In vivo small interfering RNA (siRNA) inhibition of KMT5A or CNBP potentially slowed post-MI atherosclerosis. Sympathetic denervation with 6-hydroxydopamine reduced atherosclerosis and inflammation after MI. Classical monocytes from ST-elevation MI (STEMI) patients with advanced coronary lesions expressed higher SYK and KMT5A gene levels. CONCLUSIONS: The findings underscore the crucial role of monocyte trained immunity in accelerated atherosclerosis after MI, implying that SYK in blood classical monocytes may serve as a predictive factor for the progression of atherosclerosis in STEMI patients.

Electrochemically promoted thio-Michael addition of N-substituted maleimides to thiols in an aqueous medium.

A stable and practical electrochemical method was developed to promote the thio-Michael addition of N-substituted maleimides to various thiols in an aqueous medium. This protocol was found to be excellent in terms of facile scale-up, oxidant- and catalyst-free conditions, broad substrate scopes, good functional group tolerance, and easily available substrates. Notably, a plausible reaction mechanism was derived from the results of a series of control experiments and CV studies, which indicated that a radical pathway might speed up the thio-Michael addition under constant current.

[Authenticity discrimination for Galli Gigerii Endothelium Corneum based on UPLC-MS/MS and peptidomics].

Peptidomics was employed to systematically analyze the characteristic peptides in Galli Gigerii Endothelium Corneum and its adulterants and establish a method for distinguishing Galli Gigerii Endothelium Corneum from its adulterants, including the gizzard membranes from ducks, geese, and pigeons. UPLC-Q-Exactive Orbitrap-MS was combined with multivariate statistical analysis to analyze the peptides in Galli Gigerii Endothelium Corneum and its adulterants. The structures of peptides were identified by pNovo combined with manual recognition of spectra, and synthetic peptide standards were used for validation. LC-MS/MS was used to optimize the sample pre-processing conditions, including the extraction procedure, extraction time, extraction solvents, and solvent volumes, for the characteristic peptide LESY in Galli Gigerii Endothelium Corneum. Multiple reaction monitoring(MRM) in the ESI~+ mode with m/z 511.24→269.11 and 511.24→243.13 as detection ions was employed for qualitative and quantitative analyses. The established UPLC-MS/MS method demonstrated good specificity, stability, and durability. The content of LESY in 16 batches of Galli Gigerii Endothelium Corneum samples ranged from 55.03 to 113.36 µg·g~(-1). Additionally, a qualitative detection method for the common peptide RDPVLVSR in adulterants was established with m/z 471.28→785.45 and 471.28→670.41 as the detection ions. This study established a convenient, rapid, and accurate detection method for the characteristic peptides in Galli Gigerii Endothelium Corneum and its adulterants. The method possesses good specificity, stability, and durability, providing a valuable reference for the identification and quality control of Galli Gigerii Endothelium Corneum and other traditional Chinese medicines derived from animal sources.

Catalyst-free electrochemical sulfonylation of amines with sulfonyl hydrazide in aqueous medium.

An efficient electrochemical sulfonylation of amines with sulfonyl hydrazides under exogenous-oxidant-free and catalyst-free conditions in aqueous medium was developed. A wide variety of sulfonamides were prepared via a simple electrochemical process from various cyclic or acyclic secondary amines, as well as more challenging free primary amines with equivalent amount of aryl/heteroaryl hydrazides in air under mild conditions. This protocol was found to be excellent in terms of facile scale-up, and to show great potential in the modification/synthesis of bioactive compounds. The reaction mechanism was investigated by a series of control experiments and CV studies, which indicated that the reaction might have gone through a radical pathway. Also, n-Bu4NBr served both as a supporting electrolyte and a redox agent to yield sulfonyl radical species and sulfonyl cations from sulfonyl hydrazides.

The image quality, lesion detectability, and acquisition time of 18F-FDG total-body PET/CT in oncological patients.

PURPOSE: The purpose was to investigate the effects of short acquisition time on the image quality and the lesion detectability of oncological 18F-FDG total-body PET/CT. METHODS: Nineteen oncological patients (6/13 women/men, age 65.6 ± 9.4 years) underwent total-body PET/CT on uEXPLORER scanner using 3D list mode. The administration of 18F-FDG was weight-based (4.4 MBq/kg). The acquisition time was 900 s, and PET data were reconstructed into 900-, 180-, 120-, 60-, 30-, and 18-s duration groups. The subjective PET image quality was scored using a 5-point scale (5, excellent; 1, poor) in 3 perspectives: overall quality, noise, and lesion conspicuity. The objective image quality was evaluated by SUVmax and standard deviation (SD) of the liver, SUVmax of the tumor, and tumor-to-background ratio (TBR). The lesion detectability was the percentage of identifiable lesions in the groups of 180 to 18 s using the group 900 s as reference. RESULTS: Our results showed that sufficient and acceptable subjective image quality could be achieved with 60- and 30-s groups, and good image quality scores were given to 180- and 120-s groups without significant difference. For shortened acquisition time, SD was increased, while SUVmax of tumor and TBR remained unchanged. The lesion detectability was decreased with shorter acquisition time, but the detection performance could be maintained until the 60-s group compared with the 900-s group, although the image quality degraded. CONCLUSION: The total-body PET/CT can significantly shorten the acquisition time with maintained lesion detectability and image quality.

NLRP3 inflammasome activation by Foot-and-mouth disease virus infection mainly induced by viral RNA and non-structural protein 2B.

Foot-and-mouth disease virus (FMDV) is a positive-strand RNA virus of the family Picornaviridae. Early studies show that some viruses of Picornaviridae, such as EMCV and EV71, induce NLRP3 inflammasome activation. Our current study demonstrates that FMDV induces the secretion of caspase-1 and interleukin 1 beta (IL-1ß), as well as activates the NLRP3 inflammasome in a dose- and time-dependent manner. Meanwhile, NLRP3 inflammasome can suppress FMDV replication during virus infection. Both FMDV RNA and viroporin 2B stimulate NLRP3 inflammasome activation. FMDV RNA triggers NLRP3 inflammasome through p-NF-κB/p65 pathway not dependent on RIG-I inflammasome. FMDV 2B activates NLRP3 inflammasome through elevation of intracellular ion, but not dependent on mitochondrial reactive oxygen species (ROS) and lysosomal cathepsin B. It further demonstrates that 2B viroporin activates NLRP3 inflammasome and induces IL-1ß in mice, which enhances the specific immune response against FMDV as an ideal self-adjuvant for FMD VLPs vaccine in guinea pigs. The results reveal a series of regulations between NLRP3 inflammasome complex and FMDV. Amino acids 140-145 of 2B is essential for forming an ion channel. By mutating the amino acid and changing the hydrophobic properties, the helical transmembrane region of the viroporin 2B is altered, so that the 2B is insufficient to trigger the activation of NLRP3 inflammasome. This study demonstrates the functions of FMDV RNA and 2B viroporin activate NLRP3 inflammasome and provides some useful information for the development of FMD vaccine self-adjuvant, which is also helpful for the establishment of effective prevention strategies by targeting NLRP3 inflammasome.

The role of ferroptosis in chronic intermittent hypoxia-induced liver injury in rats.

PURPOSE: Obstructive sleep apnea (OSA) has been related to an increased risk of liver injury. Ferroptosis is a form of programmed cell death implicated in multiple physiological and pathological processes. This study aimed to explore the role of ferroptosis in chronic intermittent hypoxia (CIH)-induced liver injury as well as to uncover the underlying mechanisms using a CIH rat model. METHODS: Fourteen male Sprague-Dawley rats were randomly allocated to either the normal control (NC) (n = 7) or the CIH group (n = 7). Rats were exposed to intermittent hypoxia for 8 weeks in CIH group. Liver function, histological changes, and markers of oxidative stress were evaluated. The protein levels of hypoxia-inducible factor-1α, nuclear factor E2-related factor 2 (Nrf2), Acyl-CoA synthetase long-chain family member 4 (ACSL4), and glutathione peroxidase 4 (GPX4) in liver were examined by Western blot analysis. RESULTS: CIH treatment caused significant increase of serum alanine aminotransferase, aspartate aminotransferase, and malondialdehyde (MDA). Liver MDA was significantly higher in CIH group than that in NC group. Histology showed that CIH treatment induced discernible swelled, disordered hepatocytes, necrosis, and infiltrated inflammatory cells. CIH treatment significantly reduced the expression of GPX4, while markedly up-regulated expression of ACSL4, indicating elevation in hepatic ferroptosis. In addition, the protein expression of Nrf2 in CIH group was significantly lower than that in NC group. CONCLUSIONS: Ferroptosis played a crucial role in CIH-induced liver injury. The hepatic ferroptosis in CIH rat model might be mediated by the dysregulation of Nrf2. This highlights a potential therapeutic target for the treatment of OSA-related liver injury.

Effect of chronic intermittent hypoxia on gene expression profiles of rat liver: a better understanding of OSA-related liver disease.

PURPOSE: Obstructive sleep apnea (OSA) and OSA-associated chronic intermittent hypoxia (CIH) have been suggested to be associated with increased risk of liver disease. Little is known about the biological pathophysiology and underlying molecular mechanisms. Here we use whole-genome expression profiling to explore the transcriptomic changes induced by CIH in rat liver. METHODS: Rats (n = 3) were exposed to CIH for 8 weeks and were compared with rats exposed to normoxia (n = 3). Illumina HiSeq 4000 platform was used to examine differentially expressed genes (DEGs) in the liver between control group and CIH rat model. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to validate DEGs. Biological functions of DEGs were determined by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. RESULTS: Compared with control group, 318 genes were identified to be dysregulated in the liver of CIH rat model, with 211genes upregulated and 107 genes downregulated. Bioinformatics analysis showed that these genes were extensively related to various physiologic processes such as hepatic metabolism, apoptotic process, and oxidative stress. 10 genes with 5 upregulated and 5 downregulated were selected and further verified by qRT-PCR. CONCLUSIONS: CIH resulted in altered gene expression patterns in the liver of rat. The DEGs were related to various physiological and pathological processes in CIH rat liver. These data provide a better understanding of the mechanisms and underlying molecular changes of OSA-related liver disease.

Low Dose and Low Contrast Medium Coronary CT Angiography Using Dual-Layer Spectral Detector CT.

The aim of the present study was to investigate the performance of low keV mono-energetic reconstructions in spectral coronary computed tomography angiography (CCTA) using spectral detector CT (SDCT) with reduced contrast media and radiation dose.Sixty patients were randomly assigned to Groups A and B (both n = 30) to undergo CCTA on a dual-layer SDCT with tube voltage 120 kVp and 100 kVp (average tube current: 108.5 and 73.8 mAs, respectively), with contrast media volume of 36 mL used in both groups. The mono-energetic 40-80 keV and conventional 120 kVp images in Group A and conventional 100 kVp images in Group B were reconstructed. Quantitative and qualitative image quality (IQ) were evaluated in the aortic root and distal segments of the coronary arteries.The patient characteristics were not significantly different between the two groups (all P≥ 0.47), nor was the effective radiation dose (1.5 ± 0.3 and 1.4 ± 0.3 mSv, P = 0.20). The quantitative IQ in aorta and coronary arteries of mono-energetic 40-60 keV was superior to conventional 120 kVp and 100 kVp images (all P < 0.05). The noise in spectral images was lower compared to conventional images (all P < 0.01). The subjective IQ score of 40-50 keV images was not significantly different from that of 100 kVp images (P > 0.8).The mono-energetic 40-50 keV reconstructions from spectral CCTA using SDCT provide improved IQ compared to conventional techniques while facilitating reduced radiation dose and contrast media.

Effects of PrPC on DF-1 cells' biological processes and RNA-seq-based analysis of differential genes.

To reveal the effects of PrPC on cells' biological processes and on gene expression. We established stable DF-1 (PrPC -knockdown (KD)) cells, and combined with DF-1 (wt) and DF-1 (PrPC -overexpression (OE)) cells that we previously established we studied the effects of chicken PrPC (PrPC ) on DF-1 cells' processes. Then by using high throughput sequencing technology (HTS) and bioinformatics, we analyzed the differentially expressed genes (DEGs) between these cells. The results show that compared with DF-1 (wt) and DF-1 (PrPC -scramble), DF-1 (PrPC -KD) are significantly decreased in adhesion, proliferation, formation rate of colony and cells number of colony, scratch wound healing rate, cells number of invasion and migration, S phase cell populations, but the apoptosis rate and G1 phase cell populations are significantly increased. Conversely, all of these features in DF-1 (PrPC -OE) are opposite. In addition, compared with DF-1 (wt), we found that there are totally 1055 DE genes between DF-1 (PrPC -KD) and DF-1 (PrPC -OE) cells. After Go and pathway enrichment analysis, we know that these DEGs are significantly enriched in cell, cell part, cellular process, and metabolic pathway. In short, we found that PrPC can promote DF-1 cells' processes except apoptosis. Furthermore, PrPC involves in the focal adhesion, cancer, ribosome, metabolic pathways, and so forth, and the overexpression of PrPC can promote the pathway of amoebiasis, but its down-regulation can promote the pathway of serotonergic synapse. However, the details are keeping unknown and that would be our next research.

Foot-and-mouth disease virus infection stimulates innate immune signaling in the mouse macrophage RAW 264.7 cells.

The innate immune system acts as the first line of defense against invasion by bacterial and viral pathogens. The role of macrophages in innate immune responses to foot-and-mouth disease virus (FMDV) is poorly understood. To determine the mechanism underlying activation of innate immunity after FMDV infection in macrophages, we performed FMDV infection in mouse macrophage RAW 264.7 cells and found that FMDV serotype O infection induced a cytopathic effect. We then evaluated the gene expression profile in macrophage RAW 264.7 cells after FMDV infection using systematic microarray analysis. Gene ontology annotation and enrichment analysis revealed that FMDV promoted expression in a group of genes that are enriched in innate immune response and inflammatory response processes. Further research demonstrated that FMDV serotype O infection enhanced NF-κB, Toll-like, and RIG-I-like receptor signaling pathways and proteins expression and increased transcription and expression of a series of cytokines and interferons, as proved by qRT-PCR, Western blot, ELISA, and dual-luciferase reporter assay. Our study concluded that FMDV infection triggers the innate immune response in macrophages after activation of multiple innate immune pathway receptors and proteins by FMDV serotype O, resulting in activation and secretion of a series of cytokines and interferons.

Molecular cloning and characterization of leucine aminopeptidase gene from Taenia pisiformis.

Leucine aminopeptidase (LAP, EC: 3.4.11.1) is an important metalloexopeptidase that catalyze the hydrolysis of amino-terminal leucine residues from polypeptides and proteins. In this study, a full length of cDNA encoding leucine aminopeptidase of Taenia pisiformis (TpLAP) was cloned by rapid amplification of cDNA-ends using the polymerase chain reaction (RACE-PCR) method. The full-length cDNA of the TpLAP gene is 1823 bp and contains a 1569 bp ORF encoding 533 amino acids with a putative mass of 56.4 kDa. TpLAP contains two characteristic motifs of the M17LAP family in the C-terminal sequence: the metal binding site 265-[VGKG]-271 and the catalytic domain motif 351-[NTDAEGRL]-357. The soluble GST-TpLAP protein was expressed in Escherichia coli Transetta (DE3) and four specific anti-TpLAP monoclonal antibodies (mAbs) were prepared. In enzymatic assays, the optimal activity was observed at pH 9.5 at 45 °C. GST-TpLAP displayed a hydrolyzing activity for the Leu-pNA substrate with a maximum activity of 46 U/ml. The enzymatic activity was significantly enhanced by Mn2+ and completely inhibited by 20 nM bestatin and 0.15 mM EDTA. The native TpLAP was detected specifically in ES components of adult T. pisiformis by western blotting using anti-TpLAP mAb as a probe. Quantitative real-time PCR revealed that the TpLAP gene was expressed at a high level in adult worm tissues, especially in the gravid proglottids (50.71-fold). Immunolocalization analysis showed that TpLAP was located primarily in the subtegumental parenchyma zone and the uterine wall of adult worms. Our results indicate that TpLAP is a new member of the M17LAP family and can be considered as a stage-differentially expressed protein. These findings might provide new insights into the study of the mechanisms of growth, development and survival of T. pisiformis in the final host and have potential value as an attractive target for drug therapy or vaccine intervention.

Putative roles as oncogene or tumour suppressor of the Mid-clustered microRNAs in Gallid alphaherpesvirus 2 (GaHV2) induced Marek's disease lymphomagenesis.

In the last decade, numerous microRNAs (miRNAs) have been identified in diverse virus families, particularly in herpesviruses. Gallid alphaherpesvirus 2 (GaHV2) is a representative oncogenic alphaherpesvirus that induces rapid-onset T-cell lymphomas in its natural hosts, namely Marek's disease (MD). In the GaHV2 genome there are 26 mature miRNAs derived from 14 precursors assembled into three clusters, namely the Meq-cluster, Mid-cluster and LAT-cluster. Several GaHV2 miRNAs, especially those in the Meq-cluster (e.g. miR-M4-5p), have been demonstrated to be critical in MD pathogenesis and/or tumorigenesis. Interestingly the downstream Mid-cluster is regulated and transcribed by the same promoter as the Meq-cluster in the latent phase of the infection, but the role of these Mid-clustered miRNAs in GaHV2 biology remains unclear. We have generated the deletion mutants of the Mid-cluster and of its associated individual miRNAs in GX0101 virus, a very virulent GaHV2 strain, and demonstrated that the Mid-clustered miRNAs are not essential for virus replication. Using GaHV2-infected chickens as an animal model, we found that, compared with parental GX0101 virus, the individual deletion of miR-M31 decreased the mortality and gross tumour incidence of infected chickens while the deletion individually of miR-M1 or miR-M11 unexpectedly increased viral pathogenicity or oncogenicity, similarly to the deletion of the entire Mid-cluster region. More importantly, our data further confirm that miR-M11-5p, the miR-M11-derived mature miRNA, targets the viral oncogene meq and suppresses its expression in GaHV2 infection. We report here that members of the Mid-clustered miRNAs, miR-M31-3p and miR-M11-5p, potentially act either as oncogene or tumour suppressor in MD lymphomagenesis.

Curcumin reduces lung inflammation via Wnt/ß-catenin signaling in mouse model of asthma.

OBJECTIVES: Asthma is a chronic inflammatory, heterogeneous airway disease affecting millions of people around the world. Curcumin has been found to have anti-inflammatory and antifibrosis effects. Researchers reported that curcumin regulated Wnt/ß-catenin signaling in lots of cells. However, whether curcumin regulates the levels of Wnt/ß-Catenin signaling in lung tissues and DCs (dendritic cells) remains unclear. In this study, we assessed the effects of curcumin on DCs and asthma. METHODS: C57BL/6 mice immunized with OVA (ovalbumin) were challenged thrice with an aerosol of OVA every second day for 8 days. Dexamethasone or curcumin was administered intraperitoneally to OVA-immunized C57BL/6 mice on day 24 once a day for 9 days. Mice were analyzed for effects of curcumin on asthma, inflammatory cell infiltration and cytokine levels in lung tissue. DCs were isolated from mouse bone morrow. The surface markers CD40, CD86 and CD11c of DCs was detected by FACS (fluorescence activated cell sorting) and the function of DCs was detected by mixed lymphocyte reaction. The expression of GSK-3ß and ß-catenin was detected by Western Blot. RESULTS: Results showed that OVA increased the number of inflammatory factors in BALF (bronchoalveolar lavage fluid), elevated lung inflammation scores in mice. Curcumin dose-dependently reversed the alterations induced by OVA in the asthmatic mice. Curcumin activated Wnt/ß-catenin signaling pathway in DCs and asthmatic mouse lungs. CONCLUSIONS: Curcumin could influence the morphology and function of DCs, ease asthma symptom and inflammatory reaction through the activation of Wnt/ß-catenin signaling. These results provide new evidence new evidence for application of curcumin on asthma.

Effects of ε-Polylysine on Pseudomonas Aeruginosa and Aspergillus Fumigatus Biofilm In Vitro.

BACKGROUND The antimicrobial mechanisms of ε-polylysine (EPL) against Pseudomonas aeruginosa and Aspergillus fumigatus biofilm were investigated. MATERIAL AND METHODS We assessed the changes in electric conductivity of broth and total sugar concentration, as well as changes in phosphorous metabolism and protein expression, of the 2 organisms before and after treatment with EPL. RESULTS The experimental results showed that EPL has antimicrobial activity against Pseudomonas aeruginosa and Aspergillus fumigatus, but the activity was much stronger for the former. After treatment with EPL, the electric conductivity and total sugar concentration of microbial broth increased, suggesting that EPL damages the cell membrane structure, which increases permeability of the cell membrane and release of cell components. CONCLUSIONS The consumption of phosphorous decreased in the EPL-treated organisms, which seriously affected the synthesis of important cell components such as nucleic acid and phospholipid, as well as energy metabolism.

Clinical implications of plasma Epstein-Barr virus DNA in early-stage extranodal nasal-type NK/T-cell lymphoma patients receiving primary radiotherapy.

The clinical value of plasma Epstein-Barr virus (EBV) DNA has not been evaluated in patients with early-stage extranodal nasal-type NK/T-cell lymphoma (NKTCL) receiving primary radiotherapy. Fifty-eight patients with stage I disease and 11 with stage II disease were recruited. High pretreatment EBV-DNA concentrations were associated with B-symptoms, elevated lactate dehydrogenase levels, and a high International Prognostic Index score. EBV-DNA levels significantly decreased after treatment. The 3-year overall survival (OS) rate was 82.6% for all patients. Stage I or II patients with a pretreatment EBV-DNA level of ≤ 500 copies/mL had 3-year OS and progression-free survival (PFS) rates of 97.1% and 79.0%, respectively, compared with 66.3% (P = .002) and 52.2% (P = .045) in patients with EBV-DNA levels of > 500 copies/mL. The 3-year OS and PFS rates for patients with undetectable EBV-DNA after treatment was significantly higher than patients with detectable EBV-DNA (OS, 92.0% vs 69.8%, P = .031; PFS, 77.5% vs 50.7%, P = .028). Similar results were observed in stage I patients. EBV-DNA levels correlate with tumor load and a poorer prognosis in early-stage NKTCL. The circulating EBV-DNA level could serve both as a valuable biomarker of tumor load for the accurate classification of early-stage NKTCL and as a prognostic factor.

Anticancer activity of 8-hydroxyquinoline-triphenylphosphine rhodium(III) complexes targeting mitophagy pathways.

Metallodrugs exhibiting distinct mechanisms of action compared with cisplatin hold promise for overcoming cisplatin resistance and improving the efficacy of anticancer drugs. In this study, a new series of rhodium (Rh)(III) complexes containing tris(triphenylphosphine)rhodium(I) chloride [(TPP)3RhCl] (TPP = triphenylphosphine, TPP=O = triphenylphosphine oxide) and 8-hydroxyquinoline derivatives (H-XR1-H-XR4), namely [Rh(XR1)2(TPP)Cl]·(TPP=O) (Yulin Normal University-1a [YNU-1a]), [Rh(XR2)2(TPP)Cl] (YNU-1b), [Rh(XR3)2(TPP)Cl] (YNU-1c), and [Rh(XR4)2(TPP)Cl] (YNU-1d), was synthesized and characterized via X-ray diffraction, mass spectrometry and IR. The cytotoxicity of the compounds YNU-1a-YNU-1d in Hep-G2 and HCC1806 human cancer cell lines and normal HL-7702 cell line was evaluated. YNU-1c exhibited cytotoxicity and selectivity in HCC1806 cells (IC50 = 0.13 ± 0.06 µM, selectivity factor (SF) = 384.6). The compounds YNU-1b and YNU-1c, which were selected for mechanistic studies, induced the activation of apoptotic pathways and mitophagy. In addition, these compounds released cytochrome c, cleaved caspase-3/pro-caspase-3 and downregulated the levels of mitochondrial respiratory chain complexes I/IV (M1 and M4) and ATP. The compound YNU-1c, which was selected for in vivo experiments, exhibited tumor growth inhibition (58.9 %). Importantly, hematoxylin and eosin staining and TUNEL revealed that HCC1806 tumor tissues exhibited significant apoptotic characteristics. YNU-1a-YNU-1d compounds are promising drug candidates that can be used to overcome cisplatin resistance.

Synthesis and anticancer mechanisms of four novel platinum(II) 4'-substituted-2,2':6',2''-terpyridine complexes.

Mitophagy, a selective autophagic process, has emerged as a pathway involved in degrading dysfunctional mitochondria. Herein, new platinum(II)-based chemotherapeutics with mitophagy-targeting properties are proposed. Four novel binuclear anticancer Pt(II) complexes with 4'-substituted-2,2':6',2''-terpyridine derivatives (tpy1-tpy4), i.e., [Pt2(tpy1)(DMSO)2Cl4]·CH3OH (tpy1Pt), [Pt(tpy2)Cl][Pt(DMSO)Cl3]·CH3COCH3 (tpy2Pt), [Pt(tpy3)Cl][Pt(DMSO)Cl3] (tpy3Pt), and [Pt(tpy4)Cl]Cl·CH3OH (tpy4Pt), were designed and prepared. Moreover, their potential antitumor mechanism was studied. Tpy1Pt-tpy4Pt exhibited more selective cytotoxicity against cisplatin-resistant SK-OV-3/DDP (SKO3cisR) cancer cells compared with those against ovarian SK-OV-3 (SKO3) cancer cells and normal HL-7702 liver (H702) cells. This selective cytotoxicity of Tpy1Pt-tpy4Pt was better than that of its ligands (i.e., tpy1-tpy4), the clinical drug cisplatin, and cis-Pt(DMSO)2Cl2. The results of various experiments indicated that tpy1Pt and tpy2Pt kill SKO3cisR cancer cells via a mitophagy pathway, which involves the disruption of the mitophagy-related protein expression, dissipation of the mitochondrial membrane potential, elevation of the [Ca2+] and reactive oxygen species levels, promotion of mitochondrial DNA damage, and reduction in the adenosine triphosphate and mitochondrial respiratory chain levels. Furthermore, in vivo experiments indicated that the dinuclear anticancer Pt(II) coordination compound (tpy1Pt) has remarkable therapeutic efficiency (ca. 52.4%) and almost no toxicity. Therefore, the new 4'-substituted-2,2':6',2''-terpyridine Pt(II) coordination compound (tpy1Pt) is a potential candidate for next-generation mitophagy-targeting dinuclear Pt(II)-based anticancer drugs.

First-principles calculations to investigate the impact of fluorine doping on electrochemical properties of Li-rich Li2MnO3 layered cathode materials.

Li-rich layered oxides are promising candidates for high-capacity Li-ion battery cathode materials. In this study, we employ first-principles calculations to investigate the effect of F doping on Li-rich Li2MnO3 layered cathode materials. Our findings reveal that both Li2MnO3 and Li2MnO2.75F0.25 exhibit significant volume changes (greater than 10%) during deep delithiation, which could hinder the cycling of more Li ions from these two materials. For Li2MnO3, it is observed that oxygen ions lose electrons to compensate for charge during the delithiation process, leading to a relatively high voltage plateau. After F doping, oxidation occurs in both the cationic (Mn) and anionic (O) components, resulting in a lower voltage plateau at the beginning of the charge, which can be attributed to the oxidation of Mn3+ to Mn4+. Additionally, F doping can somewhat suppress the release of oxygen in Li2MnO3, improving the stability of anionic oxidation. However, the increase of the activation barriers for Li diffusion can be observed after F doping, due to stronger electrostatic interactions between F- and Li+, which adversely affects the cycling kinetics of Li2MnO2.75F0.25. This study enhances our understanding of the impact of F doping in Li2MnO3 based on theoretical calculations.