Tunable Pt-NiO interaction-induced efficient electrocatalytic water oxidation and methanol oxidation.

Metal-support interaction engineering is considered an efficient strategy for optimizing the catalytic activity. Nevertheless, the fine regulation of metal-support interactions as well as understanding the corresponding catalytic mechanisms (particularly those of non-carbon support-based counterparts) remains challenging. Herein, a controllable adsorption-impregnation strategy was proposed for the preparation of a porous nonlayered 2D NiO nanoflake support anchored with different forms of Pt nanoarchitectures, i.e. single atoms, clusters and nanoparticles. Benefiting from the unique porous architecture of NiO nanosheets, abundant active defect sites facilitated the immobilization of Pt single atoms onto the NiO crystal, resulting in NiO lattice distortion and thus changing the valence state of Pt, chemical bonding, and the coordination environment of the metal center. The synergy of the porous NiO support and the unexpected Pt single atom-NiO interactions effectively accelerated mass transfer and reduced the reaction kinetic barriers, contributing to a significantly enhanced mass activity of 5.59 A mgPt -1 at an overpotential of 0.274 V toward the electrocatalytic oxygen evolution reaction (OER) while 0.42 A mgPt -1 at a potential of 0.7 V vs. RHE for the methanol oxidation reaction (MOR) in an alkaline system, respectively. This work may offer fundamental guidance for developing metal-loaded/dispersed support nanomaterials toward electrocatalysis through the fine regulation of metal-support interactions.

Andrographolide ameliorates sepsis-induced acute lung injury by promoting autophagy in alveolar macrophages via the RAGE/PI3K/AKT/mTOR pathway.

Autophagy in alveolar macrophages (AMs) is an important mechanism for maintaining immune homeostasis and normal lung tissue function, and insufficient autophagy in AMs may mediate the development of sepsis-induced acute lung injury (SALI). Insufficient autophagy in AMs and the activation of the NLRP3 inflammasome were observed in a mouse model with SALI induced by cecal ligation and puncture (CLP), resulting in the release of a substantial quantity of proinflammatory factors and the formation of SALI. However, after andrographolide (AG) intervention, autophagy in AMs was significantly promoted, the activation of the NLRP3 inflammasome was inhibited, the release of proinflammatory factors and pyroptosis were suppressed, and SALI was then ameliorated. In the MH-S cell model stimulated with LPS, insufficient autophagy was discovered to promote the overactivation of the NLRP3 inflammasome. AG was found to significantly promote autophagy, inhibit the activation of the NLRP3 inflammasome, and attenuate the release of proinflammatory factors. The primary mechanism of AG promoting autophagy was to inhibit the activation of the PI3K/AKT/mTOR pathway by binding RAGE to the membrane. In addition, it inhibited the activation of the NLRP3 inflammasome to ameliorate SALI. Our findings suggest that AG promotes autophagy in AMs through the RAGE/PI3K/AKT/mTOR pathway to inhibit the activation of the NLRP3 inflammasome, remodel the functional homeostasis of AMs in SALI, and exert anti-inflammatory and lung-protective effects. It has also been the first to suggest that RAGE is likely a direct target through which AG regulates autophagy, providing theoretical support for a novel therapeutic strategy in sepsis.

G-Quadruplex mRNAs Silencing with Inducible Ribonuclease Targeting Chimera for Precision Tumor Therapy.

Ribonuclease targeting chimera (RIBOTAC) represents an emerging strategy for targeted therapy. However, RIBOTAC that is selectively activated by bio-orthogonal or cell-specific triggers has not been explored. We developed a strategy of inducible RIBOTAC (iRIBOTAC) that enables on-demand degradation of G-quadruplex (G4) RNAs for precision cancer therapy. iRIBOTAC is designed by coupling an RNA G4 binder with a caged ribonuclease recruiter, which can be decaged by a bio-orthogonal reaction, tumor-specific enzyme, or metabolite. A bivalent G4 binder is engineered by conjugating a near-infrared (NIR) fluorescence G4 ligand to a noncompetitive G4 ligand, conferring fluorescence activation on binding G4s with synergistically enhanced affinity. iRIBOTAC is demonstrated to greatly knockdown G4 RNAs upon activation under bio-orthogonal or cell-specific stimulus, with dysregulation of gene expressions involving cell killing, channel regulator activity, and metabolism as revealed by RNA sequencing. This strategy also shows a crucial effect on cell fate with remarkable biochemical hallmarks of apoptosis. Mice model studies demonstrate that iRIBOTAC allows selective imaging and growth suppression of tumors with bio-orthogonal and tumor-specific controls, highlighting G4 RNA targeting and inducible silencing as a valuable RIBOTAC paradigm for cancer therapy.

Lipoproteins and metabolites in diagnosing and predicting Alzheimer's disease using machine learning.

BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disorder that poses a substantial economic burden. The Random forest algorithm is effective in predicting AD; however, the key factors influencing AD onset remain unclear. This study aimed to analyze the key lipoprotein and metabolite factors influencing AD onset using machine-learning methods. It provides new insights for researchers and medical personnel to understand AD and provides a reference for the early diagnosis, treatment, and early prevention of AD. METHODS: A total of 603 participants, including controls and patients with AD with complete lipoprotein and metabolite data from the Alzheimer's disease Neuroimaging Initiative (ADNI) database between 2005 and 2016, were enrolled. Random forest, Lasso regression, and CatBoost algorithms were employed to rank and filter 213 lipoprotein and metabolite variables. Variables with consistently high importance rankings from any two methods were incorporated into the models. Finally, the variables selected from the three methods, with the participants' age, sex, and marital status, were used to construct a random forest predictive model. RESULTS: Fourteen lipoprotein and metabolite variables were screened using the three methods, and 17 variables were included in the AD prediction model based on age, sex, and marital status of the participants. The optimal random forest modeling was constructed with "mtry" set to 3 and "ntree" set to 300. The model exhibited an accuracy of 71.01%, a sensitivity of 79.59%, a specificity of 65.28%, and an AUC (95%CI) of 0.724 (0.645-0.804). When Mean Decrease Accuracy and Gini were used to rank the proteins, age, phospholipids to total lipids ratio in intermediate-density lipoproteins (IDL_PL_PCT), and creatinine were among the top five variables. CONCLUSIONS: Age, IDL_PL_PCT, and creatinine levels play crucial roles in AD onset. Regular monitoring of lipoproteins and their metabolites in older individuals is significant for early AD diagnosis and prevention.

Screening of key immune-related gene in Parkinson's disease based on WGCNA and machine learning. / 基于WGCNAå’Œæœºå™¨å­¦ä¹ ç­›é€‰å¸•é‡‘æ£®ç— å ç–«ç›¸å ³å ³é”®åŸºå› .

OBJECTIVES: Abnormal immune system activation and inflammation are crucial in causing Parkinson's disease. However, we still don't fully understand how certain immune-related genes contribute to the disease's development and progression. This study aims to screen key immune-related gene in Parkinson's disease based on weighted gene co-expression network analysis (WGCNA) and machine learning. METHODS: This study downloaded the gene chip data from the Gene Expression Omnibus (GEO) database, and used WGCNA to screen out important gene modules related to Parkinson's disease. Genes from important modules were exported and a Venn diagram of important Parkinson's disease-related genes and immune-related genes was drawn to screen out immune related genes of Parkinson's disease. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to analyze the the functions of immune-related genes and signaling pathways involved. Immune cell infiltration analysis was performed using the CIBERSORT package of R language. Using bioinformatics method and 3 machine learning methods [least absolute shrinkage and selection operator (LASSO) regression, random forest (RF), and support vector machine (SVM)], the immune-related genes of Parkinson's disease were further screened. A Venn diagram of differentially expressed genes screened using the 4 methods was drawn with the intersection gene being hub nodes (hub) gene. The downstream proteins of the Parkinson's disease hub gene was identified through the STRING database and a protein-protein interaction network diagram was drawn. RESULTS: A total of 218 immune genes related to Parkinson's disease were identified, including 45 upregulated genes and 50 downregulated genes. Enrichment analysis showed that the 218 genes were mainly enriched in immune system response to foreign substances and viral infection pathways. The results of immune infiltration analysis showed that the infiltration percentages of CD4+ T cells, NK cells, CD8+ T cells, and B cells were higher in the samples of Parkinson's disease patients, while resting NK cells and resting CD4+ T cells were significantly infiltrated in the samples of Parkinson's disease patients. ANK1 was screened out as the hub gene. The analysis of the protein-protein interaction network showed that the ANK1 translated and expressed 11 proteins which mainly participated in functions such as signal transduction, iron homeostasis regulation, and immune system activation. CONCLUSIONS: This study identifies the Parkinson's disease immune-related key gene ANK1 via WGCNA and machine learning methods, suggesting its potential as a candidate therapeutic target for Parkinson's disease.

Whole-genome sequencing of Pseudoalteromonas piscicida 2515 revealed its antibacterial potency against Vibrio anguillarum: a preliminary invitro study.

Pseudoalteromonas piscicida 2515, isolated from Litopenaeus vannamei culture water, is a potential marine probiotic with broad anti-Vibrio properties. However, genomic information on P. piscicida 2515 is scarce. In this study, the general genomic characteristics and probiotic properties of the P. piscicida 2515 strain were analysed. In addition, we determined the antibacterial mechanism of this bacterial strain by scanning electron microscopy (SEM). The results indicated that the whole-genome sequence of P. piscicida 2515 contained one chromosome and one plasmid, including a total length of 5,541,406 bp with a G + C content of 43.24%, and 4679 protein-coding genes were predicted. Various adhesion-related genes, amino acid and vitamin metabolism and biosynthesis genes, and stress-responsive genes were found with genome mining tools. The presence of genes encoding chitin, bromocyclic peptides, lantibiotics, and sactipeptides showed the strong antibacterial activity of the P. piscicida 2515 strain. Moreover, in coculture with Vibrio anguillarum, P. piscicida 2515 displayed vesicle/pilus-like structures located on its surface that possibly participated in its bactericidal activity, representing an antibacterial mechanism. Additionally, 16 haemolytic genes and 3 antibiotic resistance genes, including tetracycline, fluoroquinolone, and carbapenem were annotated, but virulence genes encoding enterotoxin FM (entFM), cereulide (ces), and cytotoxin K were not detected. Further tests should be conducted to confirm the safety characteristics of P. piscicida 2515, including long-term toxicology tests, ecotoxicological assessment, and antibiotic resistance transfer risk assessment. Our results here revealed a new understanding of the probiotic properties and antibacterial mechanism of P. piscicida 2515, in addition to theoretical information for its application in aquaculture.

Pristine and Fe-functionalized biochar for the simultaneous immobilization of arsenic and antimony in a contaminated mining soil.

This study examined the effectiveness of pristine biochar (BC) and Fe-functionalized biochar (FBC) in remediating As-Sb co-contaminated soil, and revealed the resulting impact on soil enzymatic activities and bacterial communities. Results from incubation experiments showed that the 1.5% FBC treatment reduced the bioavailable As and Sb concentration by 13.5% and 27.1%, respectively, in compared to the control, and reduced the proportion of specifically adsorbed and amorphous Fe-Mn oxide-bound metal(loid) fractions in the treated soil. Among the BC treatments, only the 1.5% BC treatment resulted in a reduction of bioavailable As by 11.7% and Sb by 21.4%. The 0.5% BC treatment showed no significant difference. The FBC achieved high As/Sb immobilization efficiency through Fe-induced electrostatic attraction, π-π electron donor-acceptor coordination, and complexation (Fe-O(H)-As/Sb) mechanisms. Additionally, the 1.5% FBC treatment led to a 108.2% and 367.4% increase in the activities of N-acetyl-ß-glucosaminidase and urease in soils, respectively, compared to the control. Furthermore, it significantly increased the abundance of Proteobacteria (15.2%), Actinobacteriota (37.0%), Chloroflexi (21.4%), and Gemmatimonadota (43.6%) at the phylum level. Co-occurrence network analysis showed that FBC was better than BC in increasing the complexity of bacterial communities. Partial least squares path modeling further indicated that the addition of biochar treatments can affect soil enzyme activities by altering soil bacterial composition. This study suggests that FBC application offers advantages in simultaneous As and Sb immobilization and restructuring the bacterial community composition in metal(loid)-contaminated soil.

Dual-Salt Electrolyte Additive Enables High Moisture Tolerance and Favorable Electric Double Layer for Lithium Metal Battery.

The carbonate electrolyte chemistry is a primary determinant for the development of high-voltage lithium metal batteries (LMBs). Unfortunately, their implementation is greatly plagued by sluggish electrode interfacial dynamics and insufficient electrolyte thermodynamic stability. Herein, lithium trifluoroacetate-lithium nitrate (LiTFA-LiNO3 ) dual-salt additive-reinforced carbonate electrolyte (LTFAN) is proposed for stabilizing high-voltage LMBs. We reveal that 1) the in situ generated inorganic-rich electrode-electrolyte interphase (EEI) enables rapid interfacial dynamics, 2) TFA- preferentially interacts with moisture over PF6 - to strengthen the moisture tolerance of designed electrolyte, and 3) NO3 - is found to be noticeably enriched at the cathode interface on charging, thus constructing Li+ -enriched, solvent-coordinated, thermodynamically favorable electric double layer (EDL). The superior moisture tolerance of LTFAN and the thermodynamically stable EDL constructed at cathode interface play a decisive role in upgrading the compatibility of carbonate electrolyte with high-voltage cathode. The LMBs with LTFAN realize 4.3 V-NCM523/4.4 V-NCM622 superior cycling reversibility and excellent rate capability, which is the leading level of documented records for carbonate electrode.

Xanthene-based near-infrared chromophores for high-contrast fluorescence and photoacoustic imaging of dipeptidyl peptidase 4.

Near-infrared (NIR) chromophores with analyte tunable emission and absorption properties are highly desirable for developing activatable fluorescence and photoacoustic (PA) probes for bioimaging and disease diagnosis. Here we engineer a class of new chromophores by extending the π-conjugation system of a xanthene scaffold at position 7 with different electron withdrawing groups. It is demonstrated that these chromophores exhibit pH-dependent transition from a spirocyclic "closed" form to a xanthene "open" form with remarkable changes in spectral properties. We further develop fluorescence and PA probes by caging the NIR xanthene chromophores with a dipeptidyl peptidase 4 (DPPIV) substrate. In vitro and live cell studies show that these probes allow activatable fluorescence and PA detection and imaging of DPPIV activity with high sensitivity, high specificity and fast response. Moreover, these two probes allow high-contrast and highly specific imaging of DPPIV activity in a tumour-bearing mouse model in vivo via systemic administration. This study highlights the potential of a xanthene scaffold as a versatile platform for developing high-contrast fluorescence and PA molecular probes.

Triple-function eutectic solvent additive for high performance lithium metal batteries.

Rational carbonate electrolyte chemistry is critical for the development of high-voltage lithium metal batteries (LMBs). However, the implementation of traditional carbonate electrolyte is greatly hindered by the generation of an unstable electrode interphase and corrosive by-product (HF). Herein, we propose a triple-function eutectic solvent additive of N-methylacetamide (NmAc) with LiNO3 to enhance the stability and compatibility of carbonate electrolyte. Firstly, the addition of NmAc significantly improves the solubility of LiNO3 in carbonate electrolyte by forming an eutectic pair, which regulates the Li+ solvation structure and leads to dense and homogenous Li plating. Secondly, the hydrolysis of acidic PF5 is effectively alleviated due to the strong complexation of NmAc with PF5, thus reducing the generation of corrosive HF. In addition, the optimized cathode electrolyte interphase layer decreases the structural degradation and transition metal dissolution. Consequently, Li||LiNi0.6Co0.2Mn0.2O2 (NCM622) cells with the designed electrolyte deliver superior long-term cycle reversibility and excellent rate capability. This study unveils the rationale for incorporating eutectic solvent additives within carbonate electrolytes, which significantly contribute to the advancement of their practical application for high-voltage LMBs.

Near-infrared fluorogenic imaging of carbon monoxide in live cells using palladium-mediated carbonylation.

Here we develop a near infrared (NIR) fluorogenic probe for carbon monoxide (CO) detection and imaging based on palladium-mediated carbonylation using a NIR boron-dipyrromethene difluoride as a fluorophore and tetraethylene glycols as aqueous moieties. The probe is utilized to image exogenous and endogenous CO under different stimulated conditions in live cells.

Comparative Study About Different Doses of Remimazolam in Short Laparoscopic Surgery: A Randomized Controlled Double-Blind Trial.

Objective: To study the efficacy and safety of different doses of remimazolam used for induction and maintenance in short laparoscopic surgery. Methods: A randomized controlled trial was conducted between May 2021 and May 2022 on patients underwent laparoscopic surgery for 30 minutes to an hour. Based on the drug used and the infusion rate, included patients were allocated into the Low-group of remimazolam (using a constant infusion rate of 6.0 mg/kg/h for induction and the rate of 1 mg/kg/h for maintenance), the Median-group (9.0 mg/kg/h for induction, 2 mg/kg/h for maintenance), the High-group (12.0 mg/kg/h for induction, 3.0 mg/kg/h for maintenance), and the Propofol group. The postoperative extubation time was used as the primary outcome. Results: A total of 192 patients were included in the study, with 47, 48, 48, and 49 patients in the Low-, Median-, High-, and Propofol group, respectively. There was a significant difference in postoperative extubation time, with the High-group having the highest duration of 15.21±2.34 minutes compared to the Median-group (13.17±1.71 minutes, p<0.001), Low- group (12.72±1.31 minutes, p<0.001), and the Propofol group (12.24±1.23 minutes, p<0.001). No significant difference was found between the Low-group and the Propofol group, while the Median-group still showed higher postoperative extubation time compared to the Propofol group (p=0.008). Conclusion: Compared to propofol, total intravenous induction and maintenance with high and median dosages of remimazolam may prolong postoperative extubation time. Remimazolam can be safely used for induction and maintenance at various doses while not increasing the likelihood of adverse events.

Cell-Specific Degradation of Histone Deacetylase Using Warhead-Caged Proteolysis Targeting Chimeras.

Proteolysis targeting chimeras (PROTACs) have shifted the paradigm for drug development via target protein degradation. However, PROTACs may exhibit systemic toxicity to normal cells due to indiscriminate degradation and the utility of inhibitors as a warhead for protein targeting. Here, we propose a new strategy for developing activatable PROTACs for cell-specific degradation of histone deacetylase (HDAC) with minimal side effects via caging of the warhead. Molecular docking reveals that the hydroxyl group of the HDAC inhibitor is crucial for targeting. An enzyme-activatable PROTAC is designed by caging the hydroxyl group with the substrate for NAD(P)H: quinone oxidoreductase 1 (NQO1) overexpressed in cancer cells. We demonstrate that the caged PROTAC can be converted to its active form in response to NQO1. The enzyme-activatable PROTAC allows the efficient and specific degradation of HDAC6 and exerts antiproliferative activity in NQO1-positive cells. The generalizability of the design is further demonstrated by engineering a H2O2-responsive PROTAC for specific degradation of HDAC6 in cells with elevated H2O2. The strategy of caging the ligand for target proteins would afford a new dimension for developing activatable PROTACs with high specificity and minimal side effects.

Chromofungin, a chromogranin A-derived peptide, protects against sepsis-induced acute lung injury by inhibiting LBP/TLR4-dependent inflammatory signaling.

Chromofungin (CHR) is a biologically active peptide derived from chromogranin A that exhibits anti-inflammatory effects. However, it remains unclear whether and how CHR protects against sepsis-induced acute lung injury (ALI). A murine model of sepsis-induced ALI was established through cecal ligation and puncture, with intraperitoneal injection of CHR. Lung inflammation and macrophage polarization were examined by measuring the levels of cytokines and markers of M1 (CD86, inducible nitric oxide synthase [iNOS]) or M2 macrophages (arginase-1 [Arg1], resistin-like molecule α1 [Fizz1] and CD206). In vitro, mouse MH-S cells pretreated with CHR was employed to explore the interplay between the lipopolysaccharide-binding protein (LBP)/toll-like receptor 4 (TLR4) signaling pathway and M1/M2 polarity. The results revealed CHR's ability to enhance the 7-day survival rate and protect lung pathological injury in sepsis-induced ALI. CHR increased the expression of interleukin-4 and interleukin-10 but decreased the expression of tumour necrosis factor-α and interleukin-1ß. In addition, CHR notably facilitated M2 macrophage polarization, while significantly suppressingM1 polarization of alveolar macrophages. Mechanistic investigations delineated CHR's role in macrophage polarization by downregulating nuclear factor-κB expression through modulation of the LBP/TLR4 signaling pathway. Therefore, CHR may represent a novel strategy for the prevention of sepsis-induced ALI.

Genetically Encoded RNA Sensors for Ratiometric and Multiplexed Imaging of Small Molecules in Living Cells.

Genetically encoded sensors afford powerful tools for studying small molecules and metabolites in live cells. However, genetically encoded sensors with a general design remain to be developed. Here we develop genetically encoded RNA sensors with a modular design for ratiometric and multiplexed imaging of small molecules in live cells. The sensor utilizes aptazyme as a recognition module and the light-up RNA aptamer as a signal reporter. The conformation of light-up aptamers is abrogated by a blocking sequence, and aptazyme-mediated cleavage restores the correct conformation, delivering activated fluorescence for small molecule imaging. We first developed a genetically encoded ratiometric sensor using Mango aptamer as a reference and SRB2 as a reporter. It is shown that the sensor allows quantitative imaging and detection of theophylline in live cells. The generality of the design is further demonstrated for imaging other small molecules by replacing the aptazymes. Its ability for multiplexed imaging of small molecules is further explored via the integration of different small-molecule responsive aptazymes and light-up RNA aptamers. This modular design could offer a versatile platform for imaging diverse molecules in living cells.

Optimization and Validation of Reverse Transcription Recombinase-Aided Amplification (RT-RAA) for Sorghum Mosaic Virus Detection in Sugarcane.

Sorghum mosaic virus (SrMV) causes sugarcane mosaic disease and has significant adverse economic impacts on the cultivation of sugarcane. This study aimed to develop a rapid isotherm nucleic acid amplification method for detecting SrMV. Specific primers were designed to target the conserved region of the P3 gene of SrMV. The reverse transcription recombinase-aided amplification (RT-RAA) method was developed by screening primers and optimizing reaction conditions. Comparative analyses with RT-PCR demonstrated that the RT-RAA method exhibited superior specificity, sensitivity, and reliability for SrMV detection. Notably, using a standard plasmid diluted 10-fold continuously as a template, the sensitivity of RT-RAA was 100-fold higher than that of RT-PCR. Moreover, the RT-RAA reaction displayed flexibility in a temperature range of 24-49 °C, eliminating the need for expensive and complex temperature control equipment. Thus, this method could be utilized at ambient or even human body temperature. Within a short duration of 10 min at 39 °C, the target sequence of SrMV could be effectively amplified. Specificity analysis revealed no cross-reactivity between SrMV and other common sugarcane viruses detected via the RT-RAA. With its high sensitivity, rapid reaction time, and minimal equipment requirements, this method presents a promising diagnostic tool for the reliable and expedited detection of SrMV. Furthermore, it indicates broad applicability for successfully detecting other sugarcane viruses.

Silicon inhibits the upward transport of Cd in the first internode of different rice varieties in a Cd stressed farm land.

Silicon spraying on leaves can reduce the accumulation of cadmium (Cd) in rice grain. However, it has been found that not all rice varieties decrease in Cd content after silicon (Si) application. A field study was conducted to check the performance of Si on the accumulation and transport of Cd in four rice varieties. TY390 and YXY2, having 51.5%- 60.6% Cd content of grain was inhibited by foliar Si, were classified as CRS varieties; BXY9978 and YXYLS, having Cd content of grain is nonresponsive with Si, were classified as CNS varieties. The Cd contents were mainly accumulated in stem, especially in the first stem node. While foliar Si reported no changes in the Cd content of first node in four different rice varieties. Comparing the correlation between Si and Cd contents in the above part of the first internode of CRS and CNS, as well as the relative expression of Cd transport genes in the first internode suggested that first internode was the key site to effect Cd transport through Si application, and OsZIP7 is a key Cd transporter protein responsive to Si, leading to different response of Cd transport and accmulation between the CRS and the CNS varieties of rice.

Circadian clock protein Bmal1 accelerates acute myeloid leukemia by inhibiting ferroptosis through the EBF3/ALOX15 axis.

Acute myeloid leukemia (AML) is a major leukemia with high mortality. Ferroptosis is an important regulator of cancers. However, the role of ferroptosis and its regulatory mechanisms in AML remain largely unknown. In this study, we reported elevated brain and muscle ARNT-Like protein-1 (Bmal1) expression in AML patients and cell lines, and its upregulation indicated the poor survival of patients. The correlation analysis showed that Bmal1 expression was closely correlated with cytogenetics and the French-American-British subtypes, but was not correlated with age, gender and white blood cells. RSL3 reduced Bmal1 expression in HL-60 and NB4 cells. Malondialdehyde, total iron, Fe2+ , glutathione and lipid peroxidation were examined to evaluate ferroptosis. Overexpression of Bmal1 repressed RSL3-induced ferroptosis in AML cells. Bmal1 recruited Enhancer of zeste homolog 2 (EZH2) to the Early B cell factor 3 (EBF3) promoter and enhanced its methylation, thus suppressing EBF3 expression. Moreover, the knockdown of Bmal1 sensitized AML cells to RSL3-induced ferroptosis, and it was counteracted by EBF3 knockdown. Furthermore, EBF3 bound to the Arachidonate 15-pipoxygenase (ALOX15) promoter to enhance its expression, and overexpression of EBF3 enhanced RSL3-induced ferroptosis dependent on ALOX5. We established a subcutaneous AML xenograft tumor model and reported that knockdown of Bmal1 and overexpression of EBF3 restrained AML growth by promoting ALOX15-mediated ferroptosis in vivo. Collectively, Bmal1 inhibits RSL3-induced ferroptosis by promoting EZH2-mediated EBF3 methylation and suppressing the expression of EBF3 and ALOX15, thus accelerating AML.

In Situ Transformable Pro-nanotheranostic Platform for Activable Photoacoustic Imaging and Synergistic Photothermal/Chemodynamic Cancer Therapy.

Nanotheranostic platforms integrated with diagnostic and therapeutic functions have been widely developed for tumor medicine. However, the "always-on" nanotheranostic platforms suffer from poor tumor specificity, which may largely restrict therapeutic efficacy and prevent precise theranostics. Here, we develop an in situ transformable pro-nanotheranostic platform (ZnS/Cu2O@ZIF-8@PVP) by encapsulating ZnS and Cu2O nanoparticles in a metal-organic framework (MOF) nanomaterial of ZIF-8 that allows activable photoacoustic (PA) imaging and synergistic photothermal/chemodynamic therapy (PTT/CDT) of tumors in vivo. It is shown that the pro-nanotheranostic platform gradually decomposes and releases ZnS nanoparticles and Cu+ ions in acidic conditions, which spontaneously trigger a cation exchange reaction and synthesize Cu2S nanodots in situ with activated PA signals and PTT effects. Moreover, the excessive Cu+ ions function as Fenton-like catalysts and catalyze the production of highly reactive hydroxyl radicals (•OH) for CDT using elevated levels of H2O2 in tumor microenvironments (TMEs). In vivo studies demonstrate that the in situ transformable pro-nanotheranostic platform can specifically image tumors via PA and photothermal imaging and efficiently ablate tumors through synergistic CDT/PTT. Our in situ transformable pro-nanotheranostic platform could provide a new arsenal for precise theranostics in cancer therapy.

Identification and characterization of the CDK1-BMAL1-UHRF1 pathway driving tumor progression.

The abnormal regulation of BMAL1 could lead to the occurrence and progression of various tumors. However, the mechanism of phosphorylation regulation of BMAL1 in tumorigenesis remains poorly understood. In this study, we report a previously unrecognized BMAL1 dephosphorylation pathway that promotes tumor progression. BMAL1 accelerates cell proliferation, migration, and invasion of HT1080 and Calu1 cells. CDK1 binds to BMAL1 through a conserved domain and regulates the dephosphorylation of BMAL1 on Ser42 residues, but not on Ser78 or Thr224, thereby enhancing the oncogenic activity of BMAL1. Dephosphorylation of BMAL1 Ser42 promotes tumor growth and metastasis in mouse subcutaneous transplantation tumor and lung metastatic tumor models. Moreover, UHRF1 is recognized as an important target gene of BMAL1 in cancer cells. Consequently, UHRF1 depletion mimics BMAL1 deficiency with respect to tumor suppression, whereas transfection-enforced re-expression of UHRF1 restores tumor growth in BMAL1-deficient cells. These findings suggest a link between the circadian clock regulator and cancer progression.