Wogonin Alleviates DCD Liver Ischemia/Reperfusion Injury by Regulating ALOX15/iNOS-mediated Ferroptosis.

BACKGROUND: Donation after circulatory death livers are more susceptible to ischemia/reperfusion injury (IRI) because of a longer period of warm ischemia. Growing evidence now suggests that ferroptosis plays a key regulatory role in the development of IRI, so targeting ferroptosis may be an effective strategy to alleviate IRI in liver transplantation (LT). METHODS: Using donation after circulatory death LT models in rats and oxygen-glucose deprivation/reoxygenation (OGD/R) models in BRL-3A cells, we tested the effect of the Chinese medicine monomer wogonin on liver IRI and explored the specific mechanism. RESULTS: Wogonin attenuated liver IRI and increased the survival rate of rats by inhibiting lipid peroxidation and ferroptosis. Mechanistically, arachidonic acid 15-lipoxygenase-1 (ALOX15) and inducible nitric oxide synthase (iNOS) were identified as potential targets of baicalein through bioinformatics analysis combined with in vivo and in vitro experiments. This result was further confirmed by molecular docking and cellular thermal shift assays. Finally, we silenced ALOX15 and iNOS in the OGD/R cell model and found that silencing ALOX15 and iNOS could reproduce the regulatory effect of wogonin and abrogate the regulatory effect of wogonin. CONCLUSIONS: In brief, this study emphasizes that wogonin exerts a protective effect in liver IRI through the regulation of ALOX15- and iNOS-mediated ferroptosis. ALOX15 and iNOS are potential targets for intervention in IRI induced by LT, and wogonin is a drug candidate for LT patients.

A lateral flow assay strip for simultaneous detection of miRNA and exosomes in liver cancer.

By employing an aptamer as the bridge and combining catalytic hairpin assembly with the Au aggregation amplification effect, a lateral flow assay (LFA) is designed for simultaneous detection of liver cancer-associated miRNA and exosomes. The LFA can differentiate between liver cancer patients and healthy individuals with simple operation and high accuracy.

Recent progress in the development of hypoxia-inducible factor 2α (HIF-2α) modulators: Inhibitors, agonists, and degraders (2009-2024).

Hypoxia-inducible factor 2α (HIF-2α) is a critical transcription factor that regulates cellular responses under hypoxic conditions. In situations of insufficient oxygen supply or patients with Von Hippel-Lindau (VHL) mutations, HIF-2α accumulates and forms a heterodimeric complex with aryl hydrocarbon receptor nuclear translocator (ARNT, or HIF-ß). This complex further binds to coactivator p300 and interacts with hypoxia response elements (HREs) on the DNA of downstream target genes, regulating the transcription of a variety of genes (e.g. VEGFA, CCND1, CXCR4, SLC2A1, etc) involved in various processes like angiogenesis, mitochondrial metabolism, cell proliferation, and metastasis. Targeting HIF-2α holds great promise for effectively addressing solid tumors associated with aberrant oxygen-sensing pathways and hypoxia mechanisms, offering broad application prospects. In this review, we provide an overview of recent advancements (2009-2024) in HIF-2α modulators such as inhibitors, agonists, and degraders for cancer therapy. Additionally, we discuss in detail the challenges and future directions regarding HIF-2α modulators.

Beyond the heart: Cognitive and verbal outcomes in Arab children with congenital heart diseases.

BACKGROUND: This study investigates how congenital heart diseases (CHD) characteristics and interventions affect cognitive and verbal skills in Arab children, while also uncovering previously unexplored connections between these skills and the quality of life (QoL) scores as perceived by both children and parents. METHODS: A cross-sectional study was conducted in Jordan, involving 62 children with CHD aged 6-16. Data were collected through standardized intelligence tests (namely The Raven's Progressive Matrices Test and The Wechsler Intelligence Scale for Children) and QoL assessments. RESULTS: Sex, disease severity, cyanosis, CHD defect status, conducted operations, and types of interventions did not significantly influence cognitive scores. However, a significant difference was observed in Wechsler's scores between cyanotic and non-cyanotic children (p < .01) and between severe and moderate cases (p = .01). Further, a significant positive correlation was identified between Wechsler's Scores and QoL reported by parents (r = 0.33, p < .01). This correlation was particularly pronounced in the social and school functioning dimensions of QoL. CONCLUSIONS: This study highlights the need for personalized care approaches for children with CHDs based on their individual characteristics. While cognitive abilities did not directly correlate with children's QoL reports, a significant positive correlation between verbal skills and QoL reported by parents underscores the importance of effective communication in assessing a child's overall well-being. Future research should further examine the cognitive development in this population, employing neurocognitive investigations and longitudinal studies to gain a deeper understanding of their cognitive profiles and trajectories.

Role of dynamin-related protein 1-dependent mitochondrial fission in drug-induced toxicity.

Dynamin-related protein 1 (DRP1) is an essential controller of mitochondrial fission whose activity is tightly controlled to ensure balanced mitochondrial dynamics and maintain internal cellular homeostasis. Growing evidence suggests that DRP1-dependent mitochondrial fission plays a role in drug-induced toxicity (DIT). Therefore, understanding the molecular mechanisms underlying DIT and the precise regulation of DRP1 function will inform the development of potential therapeutic treatments for DIT. This review comprehensively summarizes the diverse DITs and their potential mechanism associated with DRP1-dependent mitochondrial fission and discusses in vivo and in vitro model studies of toxicity protection targeting DRP1.

The efficacy of orthokeratology lenses with smaller back optic zone diameter in myopia control. A meta-analysis.

PURPOSE: This study was conducted to determine whether orthokeratology (OK) lenses with a smaller back optic zone diameter (BOZD) could exhibit stronger myopia control effects. METHOD: A meta-analysis was registered in PROSPERO (CRD42023408184). A comprehensive systematic database search was conducted, encompassing PubMed, Cochrane Library, EMBASE, MEDLINE, Web of Science, Ovid, CNKI and CBM, to identify relevant studies up to 25 March 2023. The primary inclusion criteria for this meta-analysis were studies that investigated the myopia control effect of OK lenses with a small optical treatment area (≤5 mm). To assess the quality of the retrieved articles, two researchers evaluated them using the Cochrane bias risk assessment criteria. The primary outcome measures were the changes in axial length (AL) and refractive error, using the weighted mean differences (WMD) and 95% confidence intervals (CI) to assess differences between small and traditional back optical treatment zone groups in terms of these outcomes. RESULTS: The analysis encompassed five eligible studies, with a 1 year duration. The average difference in AL between the groups was 0.12 mm (WMD = -0.12, 95% CI [-0.16, -0.09], p < 0.00001). Likewise, the average difference in refractive error between the two groups was 0.44 D (WMD = 0.44, 95% CI [0.30, 0.57], p < 0.00001). None of the studies reported severe adverse events. CONCLUSIONS: Current evidence suggests that OK lenses with smaller back optical treatment zone are more effective in preventing myopia progression than traditional lenses. However, a longer-term evaluation is warranted.

First report of Nocardia wallacei infection in an immunocompetent patient in Zhejiang province.

Nocardiosis is an infectious disease caused by Nocardia spp., mainly affecting immunocompromised hosts. Nocardia infection is not common; especially Nocardia wallacei infection is even rarer. The patient, female, 61 years old, farmer, has been working in the field for a long time and has normal immune function. Her main clinical manifestation was persistent back pain. Chest-enhanced computed tomography showed pulmonary inflammation. Rare pathogen Nocardia wallacei was detected in alveolar lavage fluid using matrix-assisted laser destructive ionization time-of-flight mass spectrometry. She received treatment with linezolid and was discharged after her condition improved.

Extraction of phosphorus from sewage sludge ash by electrodialysis combined with wet-chemical extraction.

Phosphorus (P) recovery from sewage sludge ash (SSA) is considered to be an effective method for P recovery. In this work, P extraction and the removal of heavy metals were realized by electrodialysis. Low-cost, easily available, and environmentally friendly plant extracts were applied as suspension to reduce the inevitable secondary pollution. And the feasibility of using plant extracts was analysed by comparing with using deionized water (DI) and oxalic acid (OA) solution. When SSA was suspended in different solutions (DI, OA, and three plant extracts - Hovenia acerba (HA), Saponin (SA) and Portulaca oleracea (PO)), the effects of reaction time and plant extract concentration on P extraction and heavy metal separation of SSA under ED treatment were compared. After the process of electrodialysis, compared to other experimental groups, electrodialysis with plant extracts obtained more P released from SSA, but less P migrated to the anode chamber. However, when SSA was suspended in PO at a concentration of 80 g/L, the proportion of P transferred from SSA to the anode chamber can still reached 37.86%. In addition, the use of plant extracts as suspension had a positive effect on the removal of heavy metals, but its effect was lower than that of the oxalic acid-treated experimental group. The results indicated that the use of plant extracts for wet-chemical extraction combined with electrodialysis promoted the removal of heavy metals and the extraction of P from SSA, which is a feasible option.

[Factors associated with the care needs of the older adults based on different disability levels].

OBJECTIVE: To identify the factors associated with the care needs of the older adults aged 65-105 by age groups, and to compare these factors across different age groups. METHODS: A total of 12 244 older adults from the Chinese longitudinal healthy longevity survey (CLHLS) conducted in 2018 were included in the analyses. The participants were categorized into three age groups: young-old (aged 65-79), middle-old (aged 80-89), and oldest-old (aged 90-105). The level of disability was measured by the disability index (DI) in four dimensions, reflecting their care needs. Potential factors associated with care needs were selected based on the health ecological model (HEM), including perspectives of personal characteristics, behavioral characteristics, interpersonal network, living and working conditions, and policy environment. Multifactor analysis was performed using multinomial Logistic regression. RESULTS: Among China ' s 12 244 older adults, 43.4% had medium or high care needs. Factors for higher care needs of older adults included higher age, higher number of chronic diseases, no exercise habit, excessive sleep duration (≥9 h/d), depressive tendency, living with children or spouse, and uneducated (all P < 0.05). In addition, the young-old group who were past smokers (OR=2.009, 95% CI: 1.019-3.959), were past drinkers (OR=2.213, 95% CI: 1.141-4.291), and reported self-perceived poverty (OR=2.051, 95% CI: 1.189-3.540), had higher level of care needs. The middle-old group who were female (OR=1.373, 95% CI: 1.038-1.817), never drank alcohol (OR=1.551, 95% CI: 1.059-2.269), and were lack of medical insurance (OR=1.598, 95% CI: 1.053-2.426), and had higher level of care needs. The oldest-old group who were female (medium care needs vs. low care needs: OR=1.412, 95% CI: 1.062-1.878; high care needs vs. low care needs: OR=1.506, 95% CI: 1.137-1.993), reported self-perceived poverty (OR=2.064, 95% CI: 1.282-3.323), and were lack of medical insurance (OR=1.621, 95% CI: 1.148-2.291), and had higher level of care needs. CONCLUSION: The identical factors associated with care needs across different age groups include age, chronic disease, exercise, sleep, depression, living arrangement, and education. Smoking, alcohol consumption, and economic status are specific factors among the young-old group of the older adults, while gender and medical insurance are specific factors among the middle-old and the oldest-old group of the older adults. We recommend conducting prospective cohort studies and intervention studies among specific age groups on the above factors to provide reliable evidence for policy formulation.

Inhibition of Mettl3 ameliorates osteoblastic senescence by mitigating m6A modifications on Slc1a5 via Igf2bp2-dependent mechanisms.

Age-related osteoporosis is characterized by a marked decrease in the number of osteoblasts, which has been partly attributed to the senescence of cells of the osteoblastic lineage. Epigenetic studies have provided new insights into the mechanisms of current osteoporosis treatments and bone repair pathophysiology. N6-methyladenosine (m6A) is a novel transcript modification that plays a major role in cellular senescence and is essential for skeletal development and internal environmental stability. Bioinformatics analysis revealed that the expression of the m6A reading protein Igf2bp2 was significantly higher in osteoporosis patients. However, the role of Igf2bp2 in osteoblast senescence has not been elucidated. In this study, we found that Igf2bp2 levels are increased in ageing osteoblasts induced by multiple repetition and H2O2. Increasing Igf2bp2 expression promotes osteoblast senescence by increasing the stability of Slc1a5 mRNA and inhibiting cell cycle progression. Additionally, Mettl3 was identified as Slc1a5 m6A-methylated protein with increased m6A modification. The knockdown of Mettl3 in osteoblasts inhibits the reduction of senescence, whereas the overexpression of Mettl3 promotes the senescence of osteoblasts. We found that administering Cpd-564, a specific inhibitor of Mettl3, induced increased bone mass and decreased bone marrow fat accumulation in aged rats. Notably, in an OVX rat model, Igf2bp2 small interfering RNA delivery also induced an increase in bone mass and decreased fat accumulation in the bone marrow. In conclusion, our study demonstrated that the Mettl3/Igf2bp2-Slc1a5 axis plays a key role in the promotion of osteoblast senescence and age-related bone loss.

Genetic analysis of congenital unilateral renal agenesis in children based on next-generation sequencing.

BACKGROUND: Congenital unilateral renal agenesis (URA) is a kind of rare birth defect during fetal development with varies clinical phenotypes. The pathogenesis and the relationship between gene and phenotype are still unclear. METHODS: Ten URA fetuses were followed up after birth using postnatal renal ultrasound examination to confirm the diagnosis with nine children were URA and one was Renal Ectopy (RE). Trio- WES, CNV- seq were performed with the 10 children and their close relatives. RESULTS: There were 3 heterozygous variants of CHD7, PROKR2 and NRIP1 genes were identified in 3 children, respectively. CHD7 (c.2663T>C, p.M888T) is classified as likely pathogenic (LP), PROKR2 (c.685G>C, p.G229R) and NRIP1 (c.2705T>G, p.F902C) are classified as variants of uncertain significance (VUS). CHD7 (c.2663T>C, p.M888T) and PROKR2 (c.685G>C, p.G229R) as URA-related genes may be associated with idiopathic hypogonadotropic hypogonadism (IHH) or CHARGE syndrome (CS), and 3D-protein structure prediction revealed that the two variants may affect the stability in the CHD7 protein or PROKR2 protein, separately. The RE-related gene NRIP1 (c.2705T>G, p.F902C) may be causative of congenital anomalies of the kidneys and urinary tract (CAKUT). CONCLUSIONS: Identification of these variants can in exploring the etiology of URA or RE and improve the level of genetic counseling. IMPACTS: We performed trio-whole-exome sequencing (trio- WES) and copy number variation sequencing (CNV- seq) in 10 children, including 9 children with Unilateral Renal Agenesis and 1 with Renal Ectopy after birth. The possible pathogenic genes of URA can be screened using prenatal and postnatal diagnosis of URA fetuses and gene detection after birth. Future studies evaluating this association may lead to a better understanding of URA and elucidate exploring the etiology of URA or RE and improve the level of genetic counseling.

EDIL3/Del-1 prevents aortic dissection through enhancing internalization and degradation of apoptotic vascular smooth muscle cells.

Thoracic aortic dissection (TAD) is a severe disease, characterized by numerous apoptotic vascular smooth muscle cells (VSMCs). EDIL3/Del-1 is a secreted protein involved in macrophage efferocytosis in acute inflammation. Here, we aimed to investigate whether EDIL3 promoted the internalization and degradation of apoptotic VSMCs during TAD. The levels of EDIL3 were decreased in the serum and aortic tissue from TAD mice. Global edil3 knockout (edil3-/-) mice and edil3-/- bone marrow chimeric mice exhibited a considerable exacerbation in ß-aminopropionitrile monofumarate (BAPN)-induced TAD, accompanied with increased apoptotic VSMCs accumulating in the damaged aortic tissue. Two types of phagocytes, RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were used for in vitro efferocytosis assay. edil3-deficient phagocytes exhibited inefficient internalization and degradation of apoptotic VSMCs. Instead, EDIL3 promoted the internalization phase through interacting with phosphatidylserine (PtdSer) on apoptotic VSMCs and binding to the macrophage ITGAV/αv-ITGB3/ß3 integrin. In addition, EDIL3 accelerated the degradation phase through activating LC3-associated phagocytosis (LAP). Mechanically, following the engulfment, EDIL3 enhanced the activity of SMPD1/acid sphingomyelinase in the phagosome through blocking ITGAV-ITGB3 integrin, which facilitates phagosomal reactive oxygen species (ROS) production by NAPDH oxidase CYBB/NOX2. Furthermore, exogenous EDIL3 supplementation alleviated BAPN-induced TAD and promoted apoptotic cell clearance. EDIL3 may be a novel factor for the prevention and treatment of TAD.Abbreviations: BAPN: ß-aminopropionitrile monofumarate; BMDM: bone marrow-derived macrophage; C12FDG: 5-dodecanoylaminofluorescein-di-ß-D-galactopyranoside; CTRL: control; CYBB/NOX2: cytochrome b-245, beta polypeptide; DCFH-DA: 2',7'-dichlorofluorescin diacetate; EDIL3/Del-1: EGF-like repeats and discoidin I-like domains 3; EdU: 5-ethynyl-2'-deoxyuridine; EVG: elastic van Gieson; H&E: hematoxylin and eosin; IL: interleukin; LAP: LC3-associated phagocytosis; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; NAC: N-acetylcysteine; PtdSer: phosphatidylserine; rEDIL3: recombinant EDIL3; ROS: reactive oxygen species; SMPD1: sphingomyelin phosphodiesterase 1; TAD: thoracic aortic dissection; TEM: transmission electron microscopy; VSMC: vascular smooth muscle cell; WT: wild-type.

Millimeter-wave over fiber integrated sensing and communication system using self-coherent OFDM.

Orthogonal frequency-division multiplexing (OFDM) waveform is highly preferred as a dual-function candidate for integrated sensing and communication (ISAC) systems. However, the sensitivity to both carrier frequency offset (CFO) and phase noise greatly impedes its applications in millimeter-wave ISAC systems. Here, we propose and experimentally demonstrate a photonic millimeter-wave ISAC system employing the virtual-carrier-aided self-coherent OFDM technique, wherein a digitally-generated local oscillator is transmitted along with the OFDM signal. Then, a compact CFO-immune and phase noise-immune envelope detection method is implemented for down-converting millimeter-wave communication and radar echo signals. In experiments, a V-band ISAC system is successfully implemented with a simplified remote radio unit, using the remote photonic millimeter-wave heterodyning up-conversion for downlink and the envelope detection-assisted down-conversion for uplink (or radar echoes). In the converged transmission link with a 5-km fiber link and 2-m space link, the Kramers-Kronig (KK) receiver supports a communication data rate up to 16-Gbit/s by mitigating signal-signal beat interference (SSBI). More significantly, the SSBI leads to negligible effects on the sensing performance when classic matched filtering is adopted for target identification. Consequently, a 4.8-cm range resolution and a 4-mm range accuracy are obtained for the radar sensing function.

Reconstruction of transparent objects using phase shifting profilometry based on diffusion models.

Phase shifting profilometry is an important technique for reconstructing the three-dimensional (3D) geometry of objects with purely diffuse surfaces. However, it is challenging to measure the transparent objects due to the pattern aliasing caused by light refraction and multiple reflections inside the object. In this work, we analyze the aliasing fringe pattern formation for transparent objects and then, propose to learn the front surface light intensity distribution based on the formation principle by using the diffusion models for generating the non-aliased fringe patterns reflected from the front surface only. With the generated fringe patterns, the 3D shape of the transparent objects can be reconstructed via the conventional structured light. We show the feasibility and performance of the proposed method on the data of purely transparent objects that are not seen in the training stage. Moreover, we found it could be generalized to other cases with local-transparent and translucent objects, showing the potential capability of the diffusion based learnable framework in tackling the problems of transparent object reconstruction.

Total net-rate of 27.88 Tb/s full C-band transmission over 4,550†km using 150†km span length and high-gain EDFA amplification.

We experimentally demonstrate a total net-rate of 27.88 Tb/s for C-band wavelength-division multiplexing (WDM) transmission over an ultralong span-length of 150 km. It is the largest net capacity × span-length product of 4182 Tb/s·km for C-band, single-core, standard single-mode optical fiber transmission over a length of more than 3,000 km. A total of 99 channels, spaced at 50 GHz intervals, are employed for transmitting 32 GBaud probabilistically constellation-shaped (PCS) 64QAM signals with an information entropy of 5.5. High gain amplifiers can achieve wavelength-division multiplexing (WDM) transmission with a bandwidth of 6.25 THz, at a noise figure below 4.3 dB, without the assistance of distributed Raman amplification.

Multi-channel broadband optical chaos generation assisted by phase modulation and CFBG feedback.

In this paper, we propose a novel and simple multi-channel broadband optical chaos generation scheme based on phase modulation and chirped fiber Bragg grating (CFBG). Firstly, phase modulation is introduced to generate more new frequency components to broaden the spectrum of the phase chaos. Meanwhile, the accumulated dispersion from CFBG distorts the intensity chaos, converts phase chaos to intensity chaos, and weakens the laser relaxation oscillation. This process would lead to energy redistribution in the power spectrum, effectively increasing the chaotic bandwidth. Then, the wavelength detuning between CFBG and the semiconductor laser is introduced to enhance the chaotic bandwidth further. The experiment results show that the 10 dB bandwidths of the five channels are up to 31.0 GHz, 34.3 GHz, 36.3 GHz, 40 GHz, and 40 GHz, respectively. Note that the maximum bandwidth of the PD in our experiment is limited to 40 GHz. In addition, the multi-channel chaotic signals obtained from the experiment system are used to generate multi-channel physical random numbers. After the post-processing operations, the total rate of five parallel high-speed physical random number generation channels is 4.64 Tbit/s (160 GSa/s × 5bit × 1 channel + 160 GSa/s × 6bit × 4 channels). As far as we know, this is the highest record of using external cavity feedback semiconductor lasers to generate random numbers, which has great potential to meet the security requirements of next-generation Tbit/s optical communication systems.

Development and validation of the PLNA score to predict cytokine storm in acute-phase SFTS patients: A single-center cohort study.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease known for its high mortality rate and its correlation with Cytokine Storms (CS). Timely detection of CS is crucial for improving the prognosis of the disease. The objective of this investigation was to develop a model for identifying cytokine storms in the acute phase of SFTS. METHODS: A total of 245 patients diagnosed with SFTS were included in this study between January 2020 and July 2022. Among them, 184 patients were part of the training set, while 61 patients were part of the validation set. Variables identified by LASSO were subsequently included in a multivariate logistic regression analysis to determine independent predictors. Subsequently, a nomogram was then developed to predict the likelihood of CS in SFTS patients. The predictive efficacy and clinical applicability of the nomogram model were further assessed through ROC analysis and the DCA curve. RESULTS: Following LASSO analysis, a total of 11 indicators were included in multivariate logistic regression analysis. The findings indicated that PLT (OR 0.865, P < 0.001), LDH (OR 1.002, P < 0.001), Na+ (OR 1.155, P = 0.005), and ALT (OR 1.019, P < 0.001) serve as independently predictors of CS in the acute phase of SFTS. Furthermore, a nomogram named the PLNA was constructed by integrating these four factors. The PLNA model exhibited favorable predictive accuracy with an AUC of 0.958. Moreover, the PLNA model exhibited excellent clinical applicability in both the training and validation sets, as evidenced by the DCA curve. CONCLUSIONS: The PLNA model, constructed using clinical indicators, can predict the probability of cytokine storm in the acute phase of SFTS patients.

Meliasanines A-L, tirucallane-type triterpenoids from Melia toosendan with anti-inflammatory properties via NF-κB signaling pathway.

Meliasanines A-L, twelve previously unreported tirucallane-type triterpenoids, together with fifteen known ones, have been isolated from the stem bark of Melia toosendan. Their structures and absolute configurations were determined based on HRESIMS, and NMR, combined with calculated ECD and single-crystal X-ray diffraction analyses. Subsequently, all compounds except 10 were evaluated for their inhibitory effect on the production of nitric oxide induced by lipopolysaccharide in RAW264.7 macrophage cells. The results indicated that seven compounds (1, 13, 14, 16, 20, 22, and 23) exhibited significant NO inhibitory effects, with IC50 values ranging from 1.35 to 5.93 µM, which were more effective than the positive control indomethacin (IC50 = 13.18 µM). Moreover, the corresponding results of Western blot analysis revealed that meliasanine A (1) can significantly suppress the protein expression of inducible nitric oxide synthase and cyclooxygenase 2 in a concentration-dependent manner. The mechanism study suggested that meliasanine A exerts an anti-inflammatory effect via the nuclear factor-κB signaling pathway by suppressing phosphorylation of P65 and IκBα.

TGF-ß1 facilitates gallbladder carcinoma metastasis by regulating FOXA1 translation efficiency through m6A modification.

TGF-ß1 plays a pivotal role in the metastatic cascade of malignant neoplasms. N6-methyladenosine (m6A) stands as one of the most abundant modifications on the mRNA transcriptome. However, in the metastasis of gallbladder carcinoma (GBC), the effect of TGF-ß1 with mRNA m6A modification, especially the effect of mRNA translation efficiency associated with m6A modification, remains poorly elucidated. Here we demonstrated a negative correlation between FOXA1 and TGF-ß1 expression in GBC. Overexpression of FOXA1 inhibited TGF-ß1-induced migration and epithelial-mesenchymal transition (EMT) in GBC cells. Mechanistically, we confirmed that TGF-ß1 suppressed the translation efficiency of FOXA1 mRNA through polysome profiling analysis. Importantly, both in vivo and in vitro experiments showed that TGF-ß1 promoted m6A modification on the coding sequence (CDS) region of FOXA1 mRNA, which was responsible for the inhibition of FOXA1 mRNA translation by TGF-ß1. We demonstrated through MeRIP and RIP assays, dual-luciferase reporter assays and site-directed mutagenesis that ALKBH5 promoted FOXA1 protein expression by inhibiting m6A modification on the CDS region of FOXA1 mRNA. Moreover, TGF-ß1 inhibited the binding capacity of ALKBH5 to the FOXA1 CDS region. Lastly, our study confirmed that overexpression of FOXA1 suppressed lung metastasis and EMT in a nude mice lung metastasis model. In summary, our research findings underscore the role of TGF-ß1 in regulating TGF-ß1/FOXA1-induced GBC EMT and metastasis by inhibiting FOXA1 translation efficiency through m6A modification.

A BRD4-Targeting Photothermal Agent for Controlled Protein Degradation.

BRD4 protein plays a pivotal role in cell cycle regulation and differentiation. Disrupting the activity of BRD4 has emerged as a promising strategy for inhibiting the growth and proliferation of cancer cells. Herein, we introduced a BRD4-targeting photothermal agent for controlled protein degradation, aiming to enhance low-temperature photothermal therapy (PTT) for cancer treatment. By incorporating a BRD4 protein inhibitor into a cyanine dye scaffold, the photothermal agent specifically bond to the bromodomain of BRD4. Upon low power density laser irradiation, the agent induced protein degradation, directly destroying the BRD4 structure and inhibiting its transcriptional regulatory function. This strategy not only prolonged the retention time of the photothermal agent in cancer cells but also confined the targeted protein degradation process solely to the tumor tissue, minimizing side effects on normal tissues through the aid of exogenous signals. This work established a simple and feasible platform for future PTT agent design in clinical cancer treatment.