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1.
Inorg Chem ; 2024 May 24.
Article in English | MEDLINE | ID: mdl-38783831

ABSTRACT

Achieving high-efficiency tunable emission in a single phosphor remains a significant challenge. Herein, we report a series of Sb3+-doped all-inorganic double perovskites, Sb3+:Cs2NaScCl6, with efficient excitation-dependent emission. In 0.5%Sb3+:Cs2NaScCl6, strong blue emission with a high photoluminescence quantum yield (PLQY) of 85% is obtained under 265 nm light irradiation, which turns into bright neutral white light with a PLQY of 56% when excited at 303 nm. Spectroscopic and computational investigations were performed to reveal the mechanism of this excitation-dependent emission. Sb3+ doping induces two different excitation channels: the internal transition of Sb3+: 5s2 → 5s5p and the electron transfer transition of Sb3+: 5s → Sc3+ 3d. The former one generates excited Sb3+ ions, which can undergo efficient energy transfer to populate the host self-trapped exciton (STE) state, yielding enhanced blue emission. The latter one leads to the formation of a new STE state with the hole localized on Sb3+ and the electron delocalized on the nearest Sc3+, which accounts for the newly exhibited low-energy emission. The difference in the excitation pathways of the two emitting STE states results in the highly efficient excitation-dependent emission, making the doped systems promising anticounterfeiting materials.

2.
J Exp Clin Cancer Res ; 43(1): 152, 2024 May 30.
Article in English | MEDLINE | ID: mdl-38812060

ABSTRACT

BACKGROUND: Intrahepatic cholangiocarcinoma (ICCA) is a heterogeneous group of malignant tumors characterized by high recurrence rate and poor prognosis. Heterochromatin Protein 1α (HP1α) is one of the most important nonhistone chromosomal proteins involved in transcriptional silencing via heterochromatin formation and structural maintenance. The effect of HP1α on the progression of ICCA remained unclear. METHODS: The effect on the proliferation of ICCA was detected by experiments in two cell lines and two ICCA mouse models. The interaction between HP1α and Histone Deacetylase 1 (HDAC1) was determined using Electrospray Ionization Mass Spectrometry (ESI-MS) and the binding mechanism was studied using immunoprecipitation assays (co-IP). The target gene was screened out by RNA sequencing (RNA-seq). The occupation of DNA binding proteins and histone modifications were predicted by bioinformatic methods and evaluated by Cleavage Under Targets and Tagmentation (CUT & Tag) and Chromatin immunoprecipitation (ChIP). RESULTS: HP1α was upregulated in intrahepatic cholangiocarcinoma (ICCA) tissues and regulated the proliferation of ICCA cells by inhibiting the interferon pathway in a Signal Transducer and Activator of Transcription 1 (STAT1)-dependent manner. Mechanistically, STAT1 is transcriptionally regulated by the HP1α-HDAC1 complex directly and epigenetically via promoter binding and changes in different histone modifications, as validated by high-throughput sequencing. Broad-spectrum HDAC inhibitor (HDACi) activates the interferon pathway and inhibits the proliferation of ICCA cells by downregulating HP1α and targeting the heterodimer. Broad-spectrum HDACi plus interferon preparation regimen was found to improve the antiproliferative effects and delay ICCA development in vivo and in vitro, which took advantage of basal activation as well as direct activation of the interferon pathway. HP1α participates in mediating the cellular resistance to both agents. CONCLUSIONS: HP1α-HDAC1 complex influences interferon pathway activation by directly and epigenetically regulating STAT1 in transcriptional level. The broad-spectrum HDACi plus interferon preparation regimen inhibits ICCA development, providing feasible strategies for ICCA treatment. Targeting the HP1α-HDAC1-STAT1 axis is a possible strategy for treating ICCA, especially HP1α-positive cases.


Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Chromobox Protein Homolog 5 , Histone Deacetylase 1 , STAT1 Transcription Factor , Cholangiocarcinoma/metabolism , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/pathology , Cholangiocarcinoma/genetics , Humans , Chromobox Protein Homolog 5/metabolism , Histone Deacetylase 1/metabolism , Mice , Animals , STAT1 Transcription Factor/metabolism , Bile Duct Neoplasms/metabolism , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/pathology , Bile Duct Neoplasms/genetics , Chromosomal Proteins, Non-Histone/metabolism , Chromosomal Proteins, Non-Histone/genetics , Cell Line, Tumor , Cell Proliferation , Male , Gene Expression Regulation, Neoplastic/drug effects , Female
3.
Cell Rep Med ; 5(5): 101531, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38697105

ABSTRACT

The clinical applications of immunocytokines are severely restricted by dose-limiting toxicities. To address this challenge, here we propose a next-generation immunocytokine concept involving the design of LH05, a tumor-conditional anti-PD-L1/interleukin-15 (IL-15) prodrug. LH05 innovatively masks IL-15 with steric hindrance, mitigating the "cytokine sink" effect of IL-15 and reducing systemic toxicities associated with wild-type anti-PD-L1/IL-15. Moreover, upon specific proteolytic cleavage within the tumor microenvironment, LH05 releases an active IL-15 superagonist, exerting potent antitumor effects. Mechanistically, the antitumor efficacy of LH05 depends on the increased infiltration of CD8+ T and natural killer cells by stimulating the chemokines CXCL9 and CXCL10, thereby converting cold tumors into hot tumors. Additionally, the tumor-conditional anti-PD-L1/IL-15 can synergize with an oncolytic virus or checkpoint blockade in advanced and metastatic tumor models. Our findings provide a compelling proof of concept for the development of next-generation immunocytokines, contributing significantly to current knowledge and strategies of immunotherapy.


Subject(s)
B7-H1 Antigen , Interleukin-15 , Tumor Microenvironment , Interleukin-15/immunology , B7-H1 Antigen/metabolism , B7-H1 Antigen/immunology , B7-H1 Antigen/genetics , Animals , Humans , Mice , Tumor Microenvironment/immunology , Tumor Microenvironment/drug effects , Cell Line, Tumor , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/drug effects , Neoplasms/immunology , Neoplasms/drug therapy , Neoplasms/pathology , Immunotherapy/methods , Mice, Inbred C57BL , Female , Killer Cells, Natural/immunology , Killer Cells, Natural/drug effects , Immune Checkpoint Inhibitors/pharmacology
4.
Chemphyschem ; : e202400250, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38820005

ABSTRACT

The design and application of molecular photoswitches have attracted much attention. Herein, we performed a detailed computational study on the photoswitch benzylidene-oxazolone system based on static electronic structure calculations and on-the-fly excited-state dynamic simulations. For the Z and E isomer, we located six and four minimum energy conical intersections (MECIs) between the first excited state (S1) and the ground state (S0), respectively. Among them, the relaxation pathway driven by ring-puckering motion is the most competitive channel with the photoisomeization process, leading to the low photoisomerization quantum yield. In the dynamic simulations, about 88 % and 66 % trajectories decays from S1 to S0 for Z and E isomer, respectively within the total simulation time of ~2 ps. The photoisomeization quantum yields obtained in our study (0.20 for Z→E and 0.12 for E→Z) agree well with the experimental measured values (0.25 and 0.11), even though the number of trajectories are limited to 50. Our study sheds light on the complexity of the benzylidene-oxazolone system 's deactivation process and the competitive mechanisms among different reaction channels, which provide theoretical guidance for further design and development of benzylidene-oxazolone based molecular photoswitches.

5.
Front Oncol ; 14: 1363055, 2024.
Article in English | MEDLINE | ID: mdl-38764575

ABSTRACT

Retroperitoneal liposarcoma (RPLPS) is a rare malignant tumor that is typically treated with surgical resection. However, RPLPS often has a high rate of local recurrence, making it crucial to explore new treatment options. In this report, we present the case of a middle-aged woman who experienced seven recurrences and underwent seven surgeries following the initial resection. Currently, the patient's condition remains stable after the eighth surgery. Although there have been numerous reports of RPLPS cases both domestically and internationally, instances of repeated recurrence like this are exceptionally rare. Therefore, we have gathered the patient's case data and conducted a retrospective analysis, incorporating relevant literature, to enhance the understanding of this disease among clinical practitioners.

6.
Chem Sci ; 15(15): 5531-5538, 2024 Apr 17.
Article in English | MEDLINE | ID: mdl-38638234

ABSTRACT

Fluorescent dye based nanoparticles (NPs) have received increased interest due to their high brightness and stability. In fluorescence microscopy and assays, high signal to background ratios and multiple channels of detection are highly coveted. To this end, time-resolved imaging offers suppression of background and temporal separation of spectrally overlapping signals. Although dye based NPs and time-resolved imaging are widely used individually, the combination of the two is uncommon. This is likely due to that dye based NPs in general display shortened and non-mono-exponential lifetimes. The lower quality of the lifetime signal from dyes in NPs is caused by aggregation caused quenching (ACQ) and energy migration to dark states in NPs. Here, we report a solution to this problem by the use of the small-molecule ionic isolation lattices (SMILES) concept to prevent ACQ. Additionally, incorporation of FRET pairs of dyes locks the exciton on the FRET acceptor providing control of the fluorescence lifetime. We demonstrate how SMILES NPs with a few percent rhodamine and diazaoxatriangulenium FRET acceptors imbedded with a cyanine donor dye give identical emission spectra and high quantum yields but very different fluorescence lifetimes of 3 ns and 26 ns, respectively. The two spectrally identical NPs are easily distinguished at the single particle level in fluorescence lifetime imaging. The doping approach for dye based NPs provides predictable fluorescence lifetimes and allows for these bright imaging reagents to be used in time-resolved imaging detection modalities.

7.
Phys Chem Chem Phys ; 26(17): 13506-13514, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38651980

ABSTRACT

Fluorescent probes have become promising tools for monitoring the concentration of peroxynitrite, which is linked to many diseases. However, despite focusing on developing numerous peroxynitrite based fluorescent probes, limited emphasis is placed on their sensing mechanism. Here, we investigated the sensing mechanism of a peroxynitrite fluorescent probe, named BHID-Bpin, with a focus on the relevant excited state dynamics. The photoexcited BHID-Bpin relaxes to its ground state via an efficient nonradiative process (∼300 ps) due to the presence of a minimum energy conical intersection between its first excited state and ground state. However, upon reacting with peroxynitrite, the Bpin moiety is cleaved from BHID-Bpin and BHID is formed. The formed BHID exhibits strong dual band fluorescence which is caused by an ultrafast excited-state intramolecular proton transfer process (∼1 ps).

8.
Angew Chem Int Ed Engl ; : e202403927, 2024 Apr 17.
Article in English | MEDLINE | ID: mdl-38632085

ABSTRACT

All-inorganic metal halides with afterglow emission have attracted increasing attention due to their significantly longer afterglow duration and higher stability compared to their organic-inorganic hybrid counterparts. However, their afterglow colors have not yet reached the blue spectral region. Here, we report all-inorganic copper-doped Rb2AgBr3 single crystals with ultralong blue afterglow (>300 s) by modulating defect states through doping engineering. The introduction of copper(I) ions into Rb2AgBr3 facilitates the formation of bromine vacancies, thus increasing the density of trap states available for charge storage and enabling bright, persistent emission after ceasing the excitation. Moreover, cascade energy transfer between distinct emissive centers in the crystals results in ultra-broadband photoluminescence, not only covering the whole white light with near-unity quantum yield but also extending into the near-infrared region. This 'cocktail' of exotic light-emission properties, in conjunction with the excellent stability of copper-doped Rb2AgBr3 crystals, allowed us to demonstrate their implementation to solid-state lighting, night vision, and intelligent anti-counterfeiting.

9.
Nano Lett ; 2024 Apr 10.
Article in English | MEDLINE | ID: mdl-38598721

ABSTRACT

Realizing lattices of exciton polariton condensates has been of much interest owing to the potential of such systems to realize analogue Hamiltonian simulators and physical computing architectures. Here, we report the realization of a room temperature polariton condensate lattice using a direct-write approach. Polariton condensation is achieved in a microcavity embedded with host-guest Frenkel excitons of an organic dye (rhodamine) in a small-molecule ionic isolation lattice (SMILES). The microcavity is patterned using focused ion beam etching to realize arbitrary lattice geometries, including defect sites on demand. The band structure of the lattice and the emergence of condensation are imaged using momentum-resolved spectroscopy. The introduction of defect sites is shown to lower the condensation threshold and result in the formation of a defect band in the condensation spectrum. The present approach allows us to study periodic, quasiperiodic, and disordered polariton condensate lattices at room temperature using a direct-write approach.

10.
Biofabrication ; 16(2)2024 Mar 28.
Article in English | MEDLINE | ID: mdl-38507799

ABSTRACT

The application of additive manufacturing (AM) technology plays a significant role in various fields, incorporating a wide range of cutting-edge technologies such as aerospace, medical treatment, electronic information, and materials. It is currently widely adopted for medical services, national defense, and industrial manufacturing. In recent years, AM has also been extensively employed to produce bone scaffolds and implant materials. Through AM, products can be manufactured without being constrained by complex internal structures. AM is particularly advantageous in the production of macroscopically irregular and microscopically porous biomimetic bone scaffolds, with short production cycles required. In this paper, AM commonly used to produce bone scaffolds and orthopedic implants is overviewed to analyze the different materials and structures adopted for AM. The applications of antibacterial bone scaffolds and bone scaffolds in biologically relevant animal models are discussed. Also, the influence on the comprehensive performance of product mechanics, mass transfer, and biology is explored. By identifying the reasons for the limited application of existing AM in the biomedical field, the solutions are proposed. This study provides an important reference for the future development of AM in the field of orthopedic healthcare. In conclusion, various AM technologies, the requirements of bone scaffolds and the important role of AM in building bridges between biomaterials, additives, and bone tissue engineering scaffolds are described and highlighted. Nevertheless, more caution should be exercised when designing bone scaffolds and conducting in vivo trials, due to the lack of standardized processes, which prevents the accuracy of results and reduces the reliability of information.


Subject(s)
Biocompatible Materials , Tissue Scaffolds , Animals , Reproducibility of Results , Biocompatible Materials/pharmacology , Biocompatible Materials/chemistry , Tissue Scaffolds/chemistry , Tissue Engineering , Bone and Bones
11.
Heliyon ; 10(3): e25533, 2024 Feb 15.
Article in English | MEDLINE | ID: mdl-38333813

ABSTRACT

Background: Application of individualized positive end-expiratory pressure (PEEP) based on minimum driving pressure facilitates to prevent from postoperative pulmonary complications (PPCs). Whether lung protective ventilation strategy can reduce the risk of PPCs in COVID-19 patients remains unclear. In this study, we compared the effects of driving pressure-guided ventilation with conventional mechanical ventilation on PPCs in patients with COVID-19. Methods: Patients infected COVID-19 within 30-day before surgery were retrospectively enrolled consecutively. Patients were divided into two group: driving pressure-guided lung protective ventilation strategy group (LPVS group) and conventional mechanical ventilation group (Control group). Propensity score matching for variables selected was used by logistic regression with the nearest-neighbor method. The outcomes were the incidence of PPCs and hypoxemia in post-anesthesia care unit. Results: There was no significant difference in the baseline data between both groups (P > 0.05). The incidence of PPCs (12.73 % vs 36.36 %, χ2 = 7.068, P = 0.008) and hypoxemia [18.18 % vs 38.18 %, χ2 = 4.492, P = 0.034], and lung ultrasound scores [4.68 ± 1.60 vs 8.39 ± 1.87, t = 8.383, P < 0.001] in LPVS group were lower than control group. The PEEP, airway pressure and plateau pressure in LPVS group were higher than control group, but driving pressure and tidal volume was lower than control group, the difference was statistically significant (P < 0.05). Conclusion: Individualized PEEP ventilation strategy guided by minimum driving pressure could improve oxygenation and reduce the incidence of PPCs in surgical patients with COVID-19.

12.
13.
Angew Chem Int Ed Engl ; 63(8): e202319969, 2024 Feb 19.
Article in English | MEDLINE | ID: mdl-38179817

ABSTRACT

Most of current metal halide materials, including all inorganic and organic-inorganic hybrids, are crystalline materials with poor workability and plasticity that limit their application scope. Here, we develop a novel class of materials termed polymeric metal halides (PMHs) through introducing polycations into antimony-based metal halide materials as A-site cations. A series of PMHs with orange-yellow broadband emission and large Stokes shift originating from inorganic self-trapped excitons are successfully prepared, which meanwhile exhibit the excellent processability and formability of polymers. The versatility of these PMHs is manifested as the broad choices of polycations, the ready extension to manganese- and copper-based halides, and the tolerance to molar ratios between polycations and metal halides in the formation of PMHs. The merger of polymer chemistry and inorganic chemistry thus provides a novel generic platform for the development of metal halide functional materials.

14.
Int J Oncol ; 64(3)2024 Mar.
Article in English | MEDLINE | ID: mdl-38240103

ABSTRACT

Carcinoembryonic antigen (CEA)­related cell adhesion molecule 6 (CEACAM6) is a cell adhesion protein of the CEA family of glycosyl phosphatidyl inositol anchored cell surface glycoproteins. A wealth of research has demonstrated that CEACAM6 is generally upregulated in pancreatic adenocarcinoma, breast cancer, non­small cell lung cancer, gastric cancer, colon cancer and other cancers and promotes tumor progression, invasion and metastasis. The transcriptional expression of CEACAM6 is regulated by various factors, including the CD151/TGF­ß1/Smad3 axis, microRNA (miR)­146, miR­26a, miR­29a/b/c, miR­128, miR­1256 and DNA methylation. In addition, the N­glycosylation of CEACAM6 protein at Asn256 is mediated by α­1,6­mannosylglycoptotein 6­ß­N­acetylglucosaminyltransferase. In terms of downstream signaling pathways, CEACAM6 promotes tumor proliferation by increasing levels of cyclin D1 and cyclin­dependent kinase 4 proteins. CEACAM6 can activate the ERK1/2/MAPK or SRC/focal adhesion kinase/PI3K/AKT pathways directly or through EGFR, leading to stimulation of tumor proliferation, invasion, migration, resistance to anoikis and chemotherapy, as well as angiogenesis. This article provides a review of the expression pattern, biological function and relationship with prognosis of CEACAM6 in cancer. In summary, CEACAM6 may be a valuable diagnostic biomarker and potential therapeutic target for human cancers exhibiting overexpression of CEACAM6.


Subject(s)
Adenocarcinoma , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , MicroRNAs , Pancreatic Neoplasms , Humans , Cell Adhesion , Carcinoembryonic Antigen , Adenocarcinoma/genetics , Phosphatidylinositol 3-Kinases/metabolism , Pancreatic Neoplasms/pathology , Cell Adhesion Molecules/genetics , Cell Adhesion Molecules/metabolism , GPI-Linked Proteins/genetics , GPI-Linked Proteins/metabolism , Cell Line, Tumor , Antigens, CD/genetics
15.
Aging Dis ; 15(1): 201-225, 2024 Feb 01.
Article in English | MEDLINE | ID: mdl-37307834

ABSTRACT

Decades of research have demonstrated an incontrovertible role of amyloid-ß (Aß) in the etiology of Alzheimer's disease (AD). However, the overemphasis on the pathological impacts of Aß may obscure the role of its metabolic precursor, amyloid precursor protein (APP), as a significant hub in the occurrence and progression of AD. The complicated enzymatic processing, ubiquitous receptor-like properties, and abundant expression of APP in the brain, as well as its close links with systemic metabolism, mitochondrial function and neuroinflammation, imply that APP plays multifaceted roles in AD. In this review, we briefly describe the evolutionarily conserved biological characteristics of APP, including its structure, functions and enzymatic processing. We also discuss the possible involvement of APP and its enzymatic metabolites in AD, both detrimental and beneficial. Finally, we describe pharmacological agents or genetic approaches with the capability to reduce APP expression or inhibit its cellular internalization, which can ameliorate multiple aspects of AD pathologies and halt disease progression. These approaches provide a basis for further drug development to combat this terrible disease.


Subject(s)
Alzheimer Disease , Amyloid beta-Protein Precursor , Humans , Amyloid beta-Protein Precursor/genetics , Alzheimer Disease/genetics , Amyloid beta-Peptides/genetics , Brain/metabolism , Mitochondria/metabolism
16.
Int J Surg ; 110(1): 385-394, 2024 Jan 01.
Article in English | MEDLINE | ID: mdl-37738006

ABSTRACT

Hilar cholangiocarcinoma (HCCA) is widely considered to have a poor prognosis. In particular, combined caudate lobe resection (CLR) as a strategy for radical resection in HCCA is important for improving the R0 resection rate. However, the criteria for R0 resection, necessity of CLR, optimal extent of hepatic resection, and surgical approach are still controversial. This review aimed to summarize the findings and discuss the controversies surrounding CLR. Numerous clinical studies have shown that combined CLR treatment for HCCA improves the R0 resection rate and postoperative survival time. Whether surgery for Bismuth type I or II is combined with CLR depends on the pathological type. Considering the anatomical factors, total rather than partial CLR is recommended to achieve a higher R0 resection rate. In the resection of HCCA, a proximal ductal margin greater than or equal to 10 mm should be achieved to obtain a survival benefit. Although there is no obvious boundary between the right side (especially the paracaval portion) and the right posterior lobe of the liver, Peng's resection line can serve as a reference marker for right-sided resection. Laparoscopic resection of the caudate lobe may be safer, more convenient, accurate, and minimally invasive than open surgery, but it needs to be completed by experienced laparoscopic doctors.


Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Klatskin Tumor , Humans , Klatskin Tumor/surgery , Klatskin Tumor/pathology , Cholangiocarcinoma/surgery , Cholangiocarcinoma/pathology , Hepatectomy , Bile Duct Neoplasms/surgery , Bile Duct Neoplasms/pathology , Liver/pathology , Bile Ducts, Intrahepatic/pathology , Treatment Outcome , Retrospective Studies
17.
Clin Transl Med ; 13(12): e1502, 2023 12.
Article in English | MEDLINE | ID: mdl-38050190

ABSTRACT

BACKGROUND: Cholangiocarcinoma (CCA) refers to a collection of malignancies that are associated with a dismal prognosis. Currently, surgical resection is the only way to cure patients with CCA. Available systemic therapy is limited to gemcitabine plus cisplatin; however, this treatment is palliative in nature. Therefore, there is still a need to explore new effective therapeutic targets to intervene against CCA. METHODS: We analyzed the expression of EZH2 and the prognosis of patients in CCA. The proliferation, migration and invasion of CCA cells after gene knockdown and overexpression were examined and validated by a xenograft model and a primary CCA mouse model with corresponding gene intervention. Targeting DNA methylation, and RNA-sequencing-based transcriptomic analysis in EZH2 and SUZ12 knockout CCA cells was performed. Bisulfite sequencing polymerase chain reaction (PCR), chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) and reverse-ChIP assays were performed for research purposes. RESULTS: Increased expression of EZH2 in CCA exhibited a significantly poorer prognosis. DNA hypomethylation of the promoter and increased mRNA levels of secreted frizzled-related protein 1 (SFRP1) were observed in CCA cells following the inhibition of polycomb repressor complex 2 (PRC2), which was achieved through a knockout of EZH2, SUZ12 and EED, respectively, or treatment with GSK126 and GSK343. Targeting the SFRP1 promoter DNA hypermethylation with dCas9-DNMT3a decreased the mRNA level of SFRP1. The expression of SFRP1 is regulated by both H3K27me3 and DNA methylation and H3K27me3 plays a crucial role in promoting SFRP1 promotor DNA methylation. GSK343 is a small molecule inhibitor that targets the catalytic activity of EZH2. It effectively inhibits the progression and development of subcutaneous xenografts and primary CCA mouse models. CONCLUSION: Overall, our data strongly suggested that targeting PRC2 promotes the expression of SFRP1, thereby inhibiting the progression of CCA. KEY POINTS/HEADLIGHTS: Cholangiocarcinoma (CCA) exhibits elevated expression of EZH2, SUZ12 and EED, resulting in increased levels of H3K27me3. Targeting polycomb repressor complex 2 (PRC2) leads to the removal of H3K27me3 from the secreted frizzled-related protein 1 (SFRP1) promoter and DNA hypomethylation, thereby activating the transcription of SFRP1. Inhibiting PRC2, including the use of EZH2 inhibitors, holds promise as a potential strategy for developing anti-cancer drugs for CCA.


Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Animals , Mice , Humans , Histones/metabolism , Secreted Frizzled-Related Proteins , Enhancer of Zeste Homolog 2 Protein/genetics , Epigenesis, Genetic/genetics , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/genetics , Cholangiocarcinoma/metabolism , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/metabolism , Bile Ducts, Intrahepatic/metabolism , Bile Ducts, Intrahepatic/pathology , RNA, Messenger , DNA
18.
Transl Psychiatry ; 13(1): 396, 2023 Dec 16.
Article in English | MEDLINE | ID: mdl-38104129

ABSTRACT

Although there are indications of a trend towards less severe acute respiratory symptoms and a decline in overall lethality from the novel Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), more and more attention has been paid to the long COVID, including the increased risk of Alzheimer's disease (AD) in COVID-19 patients. In this study, we aim to investigate the involvement of N-terminal amyloid precursor protein (APP) in SARS-CoV-2-induced amyloid-ß (Aß) pathology. Utilizing both in vitro and in vivo methodologies, we first investigated the interaction between the spike protein of SARS-CoV-2 and N-terminal APP via LSPR and CoIP assays. The in vitro impacts of APP overexpression on virus infection were further evaluated in HEK293T/ACE2 cells, SH-SY5Y cells, and Vero cells. We also analyzed the pseudovirus infection in vivo in a mouse model overexpressing human wild-type APP. Finally, we evaluated the impact of APP on pseudovirus infection within human brain organoids and assessed the chronic effects of pseudovirus infection on Aß levels. We reported here for the first time that APP, the precursor of the Aß of AD, interacts with the Spike protein of SARS-CoV-2. Moreover, both in vivo and in vitro data further indicated that APP promotes the cellular entry of the virus, and exacerbates Aß-associated pathology in the APP/PS1 mouse model of AD, which can be ameliorated by N-terminal APP blockage. Our findings provide experimental evidence to interpret APP-related mechanisms underlying AD-like neuropathology in COVID-19 patients and may pave the way to help inform risk management and therapeutic strategies against diseases accordingly.


Subject(s)
Alzheimer Disease , COVID-19 , Virus Internalization , Animals , Humans , Mice , Alzheimer Disease/complications , Alzheimer Disease/virology , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Chlorocebus aethiops , COVID-19/complications , Disease Models, Animal , HEK293 Cells , Mice, Transgenic , Post-Acute COVID-19 Syndrome , Presenilin-1 , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus , Vero Cells
19.
J Phys Chem Lett ; 14(46): 10482-10488, 2023 Nov 23.
Article in English | MEDLINE | ID: mdl-37967406

ABSTRACT

The pHrodo with an "off-on" response to the changes of pH has been widely used as a fluorescent pH probe for bioimaging. The fluorescence off-on mechanism is fundamentally important for its application and further development. Herein, the sensing mechanism, especially the relevant excited-state dynamics, of pHrodo is investigated by steady-state and time-resolved spectroscopy as well as quantum chemical calculations, showing that pHrodo is best understood using the bichromophore model. Its first excited state (S1) is a charge transfer state between two chromophores. From S1, pHrodo relaxes to its ground state (S0) via an ultrafast nonradiative process (∼0.5 ps), which causes its fluorescence to be "off". After protonation, S1 becomes a localized excited state, which accounts for the fluorescence being turned "on". Our work provides photophysical insight into the sensing mechanism of pHrodo and indicates the bichromophore model might be relevant to a wide range of fluorescent probes.

20.
Phys Chem Chem Phys ; 25(46): 32002-32009, 2023 Nov 29.
Article in English | MEDLINE | ID: mdl-37975722

ABSTRACT

The high photostability of DNAs and RNAs is inextricably related to the photochemical and photophysical properties of their building blocks, nucleobases and nucleosides, which can dissipate the absorbed UV light energy in a harmless manner. The deactivation mechanism of the nucleosides, especially the decay pathways of cytidine (Cyd), has been a matter of intense debate. In the current study, we employ high-level electronic structure calculations combined with excited state non-adiabatic dynamic simulations to provide a clear picture of the excited state deactivation of Cyd in both gas phase and aqueous solution. In both environments, a barrierless decay path driven by the ring-puckering motion and a relaxation channel with a small energy barrier driven by the elongation motion of CO bond are assigned to <200 fs and sub-picosecond decay time component, respectively. The presence of ribose group has a subtle effect on the dynamic behavior of Cyd in gas phase as the ribose-to-base hydrogen/proton transfer process is energetically inaccessible with a sizable energy barrier of about 1.4 eV. However, this energy barrier is significantly reduced in water, especially when an explicit water molecule is present. Therefore, we argue that the long-lived decay channel found in aqueous solution could be assigned to the Cyd-water intermolecular hydrogen/proton transfer process. The present study postulates a novel scenario toward deep understanding the intrinsic photostability of DNAs and RNAs and provides solid evidence to disclose the long history debate of cytidine excited-state decay mechanism, especially for the assignment of experimentally observed time components.

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