In Vivo Exposure Pathways of Ambient Magnetite Nanoparticles Revealed by Machine Learning-Aided Single-Particle Mass Spectrometry.

Nanosized ultrafine particles (UFPs) from natural and anthropogenic sources are widespread and pose serious health risks when inhaled by humans. However, tracing the inhaled UFPs in vivo is extremely difficult, and the distribution, translocation, and metabolism of UFPs remain unclear. Here, we report a label-free, machine learning-aided single-particle inductively coupled plasma mass spectrometry (spICP-MS) approach for tracing the exposure pathways of airborne magnetite nanoparticles (MNPs), including external emission sources, and distribution and translocation in vivo using a mouse model. Our results provide quantitative analysis of different metabolic pathways in mice exposed to MNPs, revealing that the spleen serves as the primary site for MNP metabolism (84.4%), followed by the liver (11.4%). The translocation of inhaled UFPs across different organs alters their particle size. This work provides novel insights into the in vivo fate of UFPs as well as a versatile and powerful platform for nanotoxicology and risk assessment.

Identification of Differentially Expressed mRNAs and lncRNAs Contributes to Elucidation of Underlying Pathogenesis and Therapeutic Strategy of Recurrent Implantation Failure.

Recurrent implantation failure (RIF) is a complex and poorly understood clinical disorder characterized by failure to conceive after repeated embryo transfers. Endometrial receptivity (ER) is a prerequisite for implantation, and ER disorders are associated with RIF. However, little is known regarding the molecular mechanisms underlying ER in RIF. In the present study, RNA sequencing data from the mid-secretory endometrium of patients with and without RIF were analyzed to explore the potential long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) involved in RIF. The analysis revealed 213 and 1485 differentially expressed mRNAs and lncRNAs, respectively (fold change ≥ 2 and p < 0.05). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that these genes were mostly involved in processes related to immunity or inflammation. 5 key genes (TTR, ALB, TF, AFP, and CFTR) and a key module including 14 hub genes (AFP, ALB, APOA1, APOA2, APOB, APOH, FABP1, FGA, FGG, GC, ITIH2, SERPIND1, TF and TTR) were identified in the protein-protein interaction (PPI) network. The 5 key genes were used to further explore the lncRNA-miRNA-mRNA regulatory network. Finally, the drug ML-193 based on the 14 hub genes was identifed through the CMap. After ML-193 treatment, endometrial cell proliferation was increased, the hub genes were mostly down-regulated, and the ER marker HOXA10 was up-regulated. These results offer insights into the regulatory mechanisms of lncRNAs and mRNAs and suggest ML-193 as a therapeutic agent for RIF by enhancing ER.

The correlation between cumulative burden of mental disorders and self-harm, shame, and insight in young female patients with schizophrenia.

This study delves into the correlation between the cumulative burden of mental disorders and self-harm, shame, and insight in young female patients with schizophrenia. A prospective randomized controlled study was used to recruit 62 female schizophrenia patients who met the recruitment conditions from January 2022 to December 2023. The participants were randomly divided into an experimental group (31 cases) and a control group (31 cases) using a computer-based random number distribution method. The experimental group underwent an 8-week Mindfulness-Based Cognitive Therapy (MBCT) intervention, while the control group received conventional treatment. Data was collected using the Modified EI-SHS scale, the Link's Stigma Scale (LSS), the Five-factor Mindfulness Scale (FFMQ), and the Self-awareness and Therapeutic Attitude Questionnaire (ITAQ) before and after the intervention. One-way ANOVA and repeated measure ANOVA were used to compare and analyze the two groups of data. The experimental group exhibited a significant reduction in EI-SHS and LSS scores (100.26 ± 11.48 vs. 88.35 ± 10.09, 112.81 ± 12.30 vs. 100.50 ± 13.52, p < 0.01), coupled with significant increase in FFMQ and ITAQ scores (113.77 ± 12.25 vs. 128.31 ± 14.09, 14.03 ± 4.18 vs. 17.30 ± 2.96, p < 0.01). A positive correlation was found between overall stigma scores and mood disorder scores (r = 0.379, P < 0.011). Correlation analysis revealed a negative correlation between mindfulness (self-awareness) and stigma (r = -0.128, P = 0.025). MBCT effectively reduced stigma in young women with schizophrenia and improved coping tendencies, cognitive status, and attitudes toward mental illness, ultimately reducing the cumulative burden of mental disorders and self-harm in these patients. Increased levels of mindfulness correspond to improved cognitive status and a more positive attitude toward treatment for mental illness. It is of great value to promote MBCT in female patients with schizophrenia.

Correlation analysis between biomechanical characteristics of lower extremities during front roundhouse kick in Taekwondo and effective scores of electronic protectors.

Objective: The purpose of this study is to analyze the inherent relationship between the score values and the biomechanical characteristics of the forward kicking motion, we aim to identify the fundamental variables influencing the score values of the forward kicking motion and establish the key biomechanical factors that effectively trigger scoring in the forward kicking motion. Methods: The DaeDo electronic scoring system was used with the Vicon optical motion capture system and the Kistler 3D force platform to obtain kinematic and kinetic variables of the front roundhouse kick motion. Linear bivariate correlation analysis and principal component analysis were used to analyze the associations between kinematic, kinetic variables, and scoring values, and summarize key biomechanical factors for effectively scoring. Results: The peak ankle plantar flexion angle and knee extension torque of the kicking leg showed a significant negative correlation with scoring values (r < 0, p < 0.05), while other variables showed no statistical significance. The peak knee flexion angle and hip extension angular velocity of the supporting leg showed a significant positive correlation with scoring values (r > 0, p < 0.01), while the peak ankle plantar flexion torque showed a significant negative correlation with scoring values (r < 0, p < 0.05), and other variables showed no statistically significant correlation. The absolute values of eigenvectors of the first and second principal components, which included hip angular velocity, ankle angle, knee torque, and hip torque, were relatively large, indicating their strong influence on effective scoring triggering. Conclusion: Maintaining ankle dorsiflexion and a larger knee flexion angle in the kicking leg is favorable for triggering scoring. Higher knee flexion angle and hip extension angular velocity in the supporting leg are also advantageous for triggering scoring. "Body posture" and "Strength" are key factors that effectively trigger scoring.

KLF13 Attenuates Lipopolysaccharide-Induced Alveolar Epithelial Cell Damage by Regulating Mitochondrial Quality Control via Binding PGC-1α.

Sepsis is a clinically life-threatening syndrome, and acute lung injury is the earliest and most serious complication. We aimed to assess the role of kruppel-like factor 13 (KLF13) in lipopolysaccharide (LPS)-induced human alveolar type II epithelial cell damage and to reveal the possible mechanism related to peroxisome proliferator-activated receptor-γ co-activator 1-α (PGC-1α). In LPS-treated A549 cells with or without KLF13 overexpression or PGC-1α knockdown, cell viability was measured by a cell counting kit-8 assay. Enzyme-linked immunosorbent assay kits detected the levels of inflammatory factors, and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining measured cell apoptosis. Besides, mitochondrial reactive oxygen species (MitoSOX) and mitochondrial membrane potential were detected using MitoSOX red- and JC-1 staining. Expression of proteins related to mitochondrial quality control (MQC) was evaluated by western blot. Co-immunoprecipitation (Co-IP) assay was used to analyze the interaction between KLF13 and PGC-1α. Results indicated that KLF13 was highly expressed in LPS-treated A549 cells. KLF13 upregulation elevated the viability and reduced the levels of inflammatory factors in A549 cells exposed to LPS. Moreover, KLF13 gain-of-function inhibited LPS-induced apoptosis of A549 cells, accompanied by upregulated BCL2 expression and downregulated Bax and cleaved caspase3 expression. Furthermore, MQC was improved by KLF13 overexpression, as evidenced by decreased MitoSOX, JC-1 monomers and increased JC-1 aggregates, coupled with the changes of proteins related to MQC. In addition, Co-IP assay confirmed the interaction between KLF13 and PGC-1α. PGC-1α deficiency restored the impacts of KLF13 upregulation on the inflammation, apoptosis, and MQC in LPS-treated A549 cells. In conclusion, KLF13 attenuated LPS-induced alveolar epithelial cell inflammation and apoptosis by regulating MQC via binding PGC-1α.

Determining the extent and frequency of on-site monitoring: a bayesian risk-based approach.

BACKGROUND: On-site monitoring is a crucial component of quality control in clinical trials. However, many cast doubt on its cost-effectiveness due to various issues, such as a lack of monitoring focus that could assist in prioritizing limited resources during a site visit. Consequently, an increasing number of trial sponsors are implementing a hybrid monitoring strategy that combines on-site monitoring with centralised monitoring. One of the primary objectives of centralised monitoring, as stated in the clinical trial guidelines, is to guide and adjust the extent and frequency of on-site monitoring. Quality tolerance limits (QTLs) introduced in ICH E6(R2) and thresholds proposed by TransCelerate Biopharma are two existing approaches for achieving this objective at the trial- and site-levels, respectively. The funnel plot, as another threshold-based site-level method, overcomes the limitation of TransCelerate's method by adjusting thresholds flexibly based on site sizes. Nonetheless, both methods do not transparently explain the reason for choosing the thresholds that they used or whether their choices are optimal in any certain sense. Additionally, related Bayesian monitoring methods are also lacking. METHODS: We propose a simple, transparent, and user-friendly Bayesian-based risk boundary for determining the extent and frequency of on-site monitoring both at the trial- and site-levels. We developed a four-step approach, including: 1) establishing risk levels for key risk indicators (KRIs) along with their corresponding monitoring actions and estimates; 2) calculating the optimal risk boundaries; 3) comparing the outcomes of KRIs against the optimal risk boundaries; and 4) providing recommendations based on the comparison results. Our method can be used to identify the optimal risk boundaries within an established risk level range and is applicable to continuous, discrete, and time-to-event endpoints. RESULTS: We evaluate the performance of the proposed risk boundaries via simulations that mimic various realistic clinical trial scenarios. The performance of the proposed risk boundaries is compared against the funnel plot using real clinical trial data. The results demonstrate the applicability and flexibility of the proposed method for clinical trial monitoring. Moreover, we identify key factors that affect the optimality and performance of the proposed risk boundaries, respectively. CONCLUSION: Given the aforementioned advantages of the proposed risk boundaries, we expect that they will benefit the clinical trial community at large, in particular in the realm of risk-based monitoring.

Yolk-Shell Au NPs@Carbon Porous Nanoreactors Derived from ZIF-8: A High-Efficiency Catalyst for Three-Component Coupling Reaction.

A yolk-shell Au NPs@carbon porous nanoreactor with an active gold (Au) core and a porous carbon shell has been fabricated and demonstrates excellent high activity and cyclic stability as a heterogeneous catalyst for the three-component coupling reaction of aldehyde, amine, and alkyne. Remarkably, the unique yolk-shell nanostructure can protect gold nanoparticles (Au NPs) from aggregation, allow for efficient mass transport, and benefit substrate enrichment, giving rise to enhanced activity, stability, and recyclability.

Targeted inhibition of DHODH is synergistic with BCL2 blockade in HGBCL with concurrent MYC and BCL2 rearrangement.

High-grade B-cell lymphoma (HGBCL), the subtype of non-Hodgkin lymphoma, to be relapsed or refractory in patients after initial therapy or salvage chemotherapy. Dual dysregulation of MYC and BCL2 is one of the important pathogenic mechanisms. Thus, combined targeting of MYC and BCL2 appears to be a promising strategy. Dihydroorotate dehydrogenase (DHODH) is the fourth rate-limiting enzyme for the de novo biosynthesis of pyrimidine. It has been shown to be a potential therapeutic target for multiple diseases. In this study, the DHODH inhibitor brequinar exhibited growth inhibition, cell cycle blockade, and apoptosis promotion in HGBCL cell lines with MYC and BCL2 rearrangements. The combination of brequinar and BCL2 inhibitors venetoclax had a synergistic inhibitory effect on the survival of DHL cells through different pathways. Venetoclax could upregulate MCL-1 and MYC expression, which has been reported as a resistance mechanism of BCL2 inhibitors. Brequinar downregulated MCL-1 and MYC, which could potentially overcome drug resistance to venetoclax in HGBCL cells. Furthermore, brequinar could downregulate a broad range of genes, including ribosome biosynthesis genes, which might contribute to its anti-tumor effects. In vivo studies demonstrated synergetic tumor growth inhibition in xenograft models with brequinar and venetoclax combination treatment. These results provide preliminary evidence for the rational combination of DHODH and BCL2 blockade in HGBCL with abnormal MYC and BCL2.

Continuous Optical Zoom Compound Eye Imaging Using Alvarez Lenses Actuated by Dielectric Elastomers.

The compound eye is a natural multi-aperture optical imaging system. In this paper, a continuous optical zoom compound eye imaging system based on Alvarez lenses is proposed. The main optical imaging part of the proposed system consists of a curved Alvarez lens array (CALA) and two Alvarez lenses. The movement of the CALA and two Alvarez lenses perpendicular to the optical axis is realized by the actuation of the dielectric elastomers (DEs). By adjusting the focal length of the CALA and the two Alvarez lenses, the proposed system can realize continuous zoom imaging without any mechanical movement vertically to the optical axis. The experimental results show that the paraxial magnification of the target can range from ∼0.30× to ∼0.9×. The overall dimensions of the optical imaging part are 54 mm × 36 mm ×60 mm (L × W × H). The response time is 180 ms. The imaging resolution can reach up to 50 lp/mm during the optical zoom process. The proposed continuous optical zoom compound eye imaging system has potential applications in various fields, including large field of view imaging, medical diagnostics, machine vision, and distance detection.

The role of magnesium in the pathogenesis of osteoporosis.

Magnesium (Mg), a nutritional element which is essential for bone development and mineralization, has a role in the progression of osteoporosis. Osteoporosis is a multifactorial disease characterized by significant deterioration of bone microstructure and bone loss. Mg deficiency can affect bone structure in an indirect way through the two main regulators of calcium homeostasis (parathyroid hormone and vitamin D). In human osteoblasts (OBs), parathyroid hormone regulates the expression of receptor activator of nuclear factor-κ B ligand (RANKL) and osteoprotegerin (OPG) to affect osteoclast (OC) formation. In addition, Mg may also affect the vitamin D3 -mediated bone remodeling activity. vitamin D3 usually coordinates the activation of the OB and OC. The unbalanced activation OC leads to bone resorption. The RANK/RANKL/OPG axis is considered to be a key factor in the molecular mechanism of osteoporosis. Mg participates in the pathogenesis of osteoporosis by affecting the regulation of parathyroid hormone and vitamin D levels to affect the RANK/RANKL/OPG axis. Different factors affecting the axis and enhancing OC function led to bone loss and bone tissue microstructure damage, which leads to the occurrence of osteoporosis. Clinical research has shown that Mg supplementation can alleviate the symptoms of osteoporosis to some extent.

Ultrathin cobalt-based nanosheets containing surface oxygen promoted near-complete nitrate removal.

Electrocatalytic nitrate removal offers a sustainable approach to alleviate nitrate pollution and to boost the anthropogenic nitrogen cycle, but it still suffers from limited removal efficiency at high rates, especially at low levels of nitrate. Herein, we report the near-complete removal of low-level nitrate (10-200 ppm) within 2 h using ultrathin cobalt-based nanosheets (CoNS) containing surface oxygen, which was fabricated from in-situ electrochemical reconstruction of conventional nanosheets. The average nitrate removal of 99.7 % with ammonia selectivity of 98.2 % in 9 cyclic runs ranked in the best of reported catalysts. Powered by a solar cell under the winter sun, the full-cell nitrate electrolysis system, equipped with ultrathin CoNS, achieved 100 % nitrogen gas selectivity and 99.6 % total nitrogen removal. The in-situ Fourier Transform Infrared included experiments and theoretical computations revealed that in-situ electrochemical reconstruction not only increased electrochemical active surface area but also constructed surface oxygen in active sites, leading to enhanced stabilization of nitrate adsorption in a symmetry breaking configuration and charge transfer, contributing to near-complete nitrate removal on ultrathin CoNS. This work provides a strategy to design ultrathin nanocatalysts for nitrate removal.

A review of electrooxidation systems treatment of poly-fluoroalkyl substances (PFAS): electrooxidation degradation mechanisms and electrode materials.

The prevalence of polyfluoroalkyls and perfluoroalkyls (PFAS) represents a significant challenge, and various treatment techniques have been employed with considerable success to eliminate PFAS from water, with the ultimate goal of ensuring safe disposal of wastewater. This paper first describes the most promising electrochemical oxidation (EO) technology and then analyses its basic principles. In addition, this paper reviews and discusses the current state of research and development in the field of electrode materials and electrochemical reactors. Furthermore, the influence of electrode materials and electrolyte types on the deterioration process is also investigated. The importance of electrode materials in ethylene oxide has been widely recognised, and therefore, the focus of current research is mainly on the development of innovative electrode materials, the design of superior electrode structures, and the improvement of efficient electrode preparation methods. In order to improve the degradation efficiency of PFOS in electrochemical systems, it is essential to study the oxidation mechanism of PFOS in the presence of ethylene oxide. Furthermore, the factors influencing the efficacy of PFAS treatment, including current density, energy consumption, initial concentration, and other parameters, are clearly delineated. In conclusion, this study offers a comprehensive overview of the potential for integrating EO technology with other water treatment technologies. The continuous development of electrode materials and the integration of other water treatment processes present a promising future for the widespread application of ethylene oxide technology.

Effects of axial loading and positions on lumbar spinal stenosis: an MRI study using a new axial loading device.

OBJECTIVE: A new axial loading device was used to investigate the effects of axial loading and positions on lumbar structure and lumbar spinal stenosis. METHODS: A total of 40 patients sequentially underwent 4 examinations: (1) the psoas-relaxed position MRI, (2) the extended position MRI, (3) the psoas-relaxed position axial loading MRI, (4) the extended position axial loading MRI. The dural sac cross-sectional area, sagittal vertebral canal diameter, disc height and ligamentum flavum thickness of L3-4, L4-5, L5-S1 and lumbar lordosis angle were measured and compared. A new device with pneumatic shoulder-hip compression mode was used for axial loading. RESULTS: In the absence of axial loading, there was a significant reduction in dural sac cross-sectional area with extension only seen at the L3-4 (p = 0.033) relative to the dural sac area in the psoas-relaxed position. However, with axial loading, there was a significant reduction in dural sac cross-sectional area at all levels in both psoas-relaxed (L3-4, p = 0.041; L5-S1, p = 0.005; L4-5, p = 0.002) and extension (p < 0.001) positions. The sagittal vertebral canal diameter and disc height were significantly reduced at all lumbar levels with axial loading and extension (p < 0.001); however, in psoas-relaxed position, the sagittal vertebral canal diameter was only reduced with axial loading at L3-4 (p = 0.018) and L4-5 (p = 0.011), and the disc height was reduced with axial-loading at all levels (L3-4, p = 0.027; L5-S1, p = 0.001; L4-5, p < 0.001). The ligamentum flavum thickness and lumbar lordosis in extension position had a statistically significant increase compared to psoas-relaxed position with or without axial loading (p < 0.001). CONCLUSION: Both axial loading and extension of lumbar may exacerbate lumbar spinal stenosis. Axial loading in extension position could maximally aggravate lumbar spinal stenosis, but may cause some patients intolerable. For those patients, axial loading MRI in psoas-relaxed position may be a good choice.

The incidence of stroke and contribution of risk factors for stroke in high-risk stroke population in southwestern China.

OBJECTIVE: To estimate the incidence of stroke and determine the role that risk factors play in the high-risk stroke populace in southwest China. METHODS: This research employed a prospective cohort design that focused on the community. Eight communities in southwest China were selected randomly for this study. The residents aged 40 years and older who volunteered to participate were surveyed through face-to-face interviews. Those with a history of stroke or at least three of the eight stroke-related risk factors were categorized as the high-risk stroke population. A total of 2698 high-risk individuals were included in the study after a 4.7-year follow-up period. The incidence of stroke and the association between risk variables and stroke occurrence were estimated. RESULTS: During 4.7-year follow-up, the incidence of total stroke, ischemic stroke, and hemorrhagic stroke in high-risk stroke population were 5.0 %, 4.4 % and 0.9 % respectively. It should be noted that some participants experienced both cerebral infarction and cerebral hemorrhage during the follow-up period. The multivariate analytic model revealed that a personal history of stroke (OR=3.397, 95 % CI 2.365-4.878, p<.001) was substantially linked with an elevated risk of overall stroke. This correlation remained consistent for both ischemic and hemorrhagic stroke. CONCLUSIONS: This study revealed a high prevalence and incidence of stroke among a high-risk group in southwestern China. Furthermore, it demonstrated that individuals with a personal history of stroke are at an elevated risk of future stroke, suggesting the need for additional precautions in this population.

X-ray activated near-infrared persistent luminescence nanoparticles for trimodality in vivo imaging.

As promising luminescence nanoparticles, near-infrared (NIR) persistent luminescence nanoparticles (PLNPs) have received extensive attention in the field of high-sensitivity bioimaging in recent years. However, NIR PLNPs face problems such as short excitation wavelengths and single imaging modes, which limit their applications in in vivo reactivated imaging and multimodal imaging. Here, we report for the first time novel Gd2GaTaO7:Cr3+,Yb3+ (GGTO) NIR PLNPs that integrate X-ray activated NIR persistent luminescence (PersL), high X-ray attenuation and excellent magnetic properties into a single nanoparticle (NP). In this case, Cr3+ is used as the luminescence center. The co-doped Yb3+ and coating effectively enhance the X-ray activated NIR PersL. At the same time, the presence of the high-Z element Ta also makes the GGTO NPs exhibit high X-ray attenuation performance, which can be used as a CT contrast agent to achieve in vivo CT imaging. In addition, since the matrix contains a large amount of Gd, the GGTO NPs show remarkable magnetic properties, which can realize in vivo MR imaging. GGTO NPs combine the trimodal benefits of X-ray reactivated PersL, CT and MR imaging and are suitable for single or combined applications that require high sensitivity and spatial resolution imaging.

Shen-Qi-Ling-Bi Decoction Inhibits Colorectal Cancer Cell Growth by Inducing Ferroptosis Through Inactivation of PI3K/AKT Signaling Pathway.

Colorectal cancer (CRC) is a common malignancy with poor prognosis. Shen-Qi-Ling-Bi Decoction (SQLB), a classic traditional Chinese medicine (TCM) formula, was found to exert antitumor effects in CRC. This study aimed to explore the biological functions of SQLB in CRC. Cell Counting Kit 8 (CCK-8), wound healing, and transwell invasion assays in vitro were used to evaluate the antitumor effects of SQLB in CRC cells. In addition, ferroptosis in CRC cells was determined by evaluating Fe2+ content and lipid ROS, MDA, and GSH levels. SQLB treatment partially reduced CRC cell proliferation, migration, and invasion; however, a ferroptosis inhibitor, ferrostatin-1 (Fer-1), abolished these effects. In addition, SQLB treatment triggered CRC cell ferroptosis, as evidenced by increased Fe2+, lipid ROS, and MDA levels and decreased GSH levels; conversely, these levels were reversed by Fer-1. Furthermore, SQLB notably suppressed tumor growth in nude mice in vivo. Meanwhile, SQLB decreased phosphorylated PI3K and AKT levels, downregulated Nrf2, GPX4, and SLC7A11 levels, and upregulated ACSL4 levels in CRC cells and in tumor tissues; however, these effects were reversed by Fer-1. Collectively, SQLB inhibited CRC cell proliferation, invasion, and migration by triggering ferroptosis through inactivation of the PI3K/AKT signaling pathway. These findings demonstrate a novel mechanism of action for SQLB in the treatment of CRC.

Stable engraftment, as well as graft versus host disease-free and relapse-free survival brought by the combination of CD7 targeted universal chimeric antigen receptor-T, and donor hemopoietic stem cells: Indication of a case report.

CD7 targeted CAR-T has demonstrated potential in the treatment of T cell malignancies but no study has been reported about its potential in the prophylaxis of GVHD in allo-HSCT. Here we reported a special case that a boy diagnosed with refractory acute T lymphoblastic leukemia (T-ALL) was treated with universal CD7 targeted CAR-T (CD7 UCAR-T) and parent-derived peripheral blood stem cells (PBSCs). Complete remission and full engraftment of donor was observed. In the later four months of follow-up, in the absence of any immunodepression treatment, no signs of GVHD were observed. This case initially demonstrates the potential of CD7 UCAR-T in the prophylaxis of GVHD.

Thymoquinone affects hypoxia-inducible factor-1α expression in pancreatic cancer cells via HSP90 and PI3K/AKT/mTOR pathways.

BACKGROUND: Pancreatic cancer (PC) is associated with some of the worst prognoses of all major cancers. Thymoquinone (TQ) has a long history in traditional medical practice and is known for its anti-cancer, anti-inflammatory, anti-fibrosis and antioxidant pharmacological activities. Recent studies on hypoxia-inducible factor-1α (HIF-1α) and PC have shown that HIF-1α affects the occurrence and development of PC in many aspects. In addition, TQ could inhibit the development of renal cancer by decreasing the expression of HIF-1α. Therefore, we speculate whether TQ affects HIF-1α expression in PC cells and explore the mechanism. AIM: To elucidate the effect of TQ in PC cells and the regulatory mechanism of HIF-1α expression. METHODS: Cell counting kit-8 assay, Transwell assay and flow cytometry were performed to detect the effects of TQ on the proliferative activity, migration and invasion ability and apoptosis of PANC-1 cells and normal pancreatic duct epithelial (hTERT-HPNE) cells. Quantitative real-time polymerase chain reaction and western blot assay were performed to detect the expression of HIF-1α mRNA and protein in PC cells. The effects of TQ on the HIF-1α protein initial expression pathway and ubiquitination degradation in PANC-1 cells were examined by western blot assay and co-immunoprecipitation. RESULTS: TQ significantly inhibited proliferative activity, migration, and invasion ability and promoted apoptosis of PANC-1 cells; however, no significant effects on hTERT-HPNE cells were observed. TQ significantly reduced the mRNA and protein expression levels of HIF-1α in PANC-1, AsPC-1, and BxPC-3 cells. TQ significantly inhibited the expression of the HIF-1α initial expression pathway (PI3K/AKT/mTOR) related proteins, and promoted the ubiquitination degradation of the HIF-1α protein in PANC-1 cells. TQ had no effect on the hydroxylation and von Hippel Lindau protein mediated ubiquitination degradation of the HIF-1α protein but affected the stability of the HIF-1α protein by inhibiting the interaction between HIF-1α and HSP90, thus promoting its ubiquitination degradation. CONCLUSION: The regulatory mechanism of TQ on HIF-1α protein expression in PC cells was mainly to promote the ubiquitination degradation of the HIF-1α protein by inhibiting the interaction between HIF-1α and HSP90; Secondly, TQ reduced the initial expression of HIF-1α protein by inhibiting the PI3K/AKT/mTOR pathway.

Ratiometric fluorescence and colorimetric strategies for assessing activity of butyrylcholinesterase in human serum using g-C3N4 nanosheets, silver ion and o-phenylenediamine.

Ratiometric fluorescence and colorimetric strategies for detecting activity of butyrylcholinesterase (BChE) in human serum were developed by using g-C3N4 nanosheets, silver ion (Ag+) and o-phenylenediamine (OPD) as chromogenic agents. The oxidation-reduction reaction of OPD and Ag+ generates 2,3-diaminophenazine (oxOPD). Under exciation at 370 nm, g-C3N4 nanosheets and oxOPD emit fluorescence at 440 nm (F440) and 560 nm (F560), respectively. Additionally, oxOPD exhibits quenching ability towards g-C3N4 nanosheets via photoinduced electron transfer (PET) process. Thiocholine (TCh), as a product of BChE-catalyzed hydrolysis reaction of butylthiocholine iodide (BTCh), can coordinate with Ag+ intensively, and consequently diminish the amount of free Ag+ in the testing system. Less amount of free Ag+ leads to less production of oxOPD, resulting in less fluorescence quenching towards g-C3N4 nanosheets as well as less fluorescence emission of oxOPD. Therefore, by using g-C3N4 nanosheets and oxOPD as fluorescence indicators, the intensity ratio of their fluorescence (F440/F560) was calculated and employed to evaluate the activity of BChE. Similarly, the color variation of oxOPD indicated by the absorbance at 420 nm (ΔA420) was monitored for the same purpose. These strategies were validated to be sensitive and selective for detecting BChE activity in human serum, with limits of detection (LODs) of 0.1 U L-1 for ratiometric fluorescence mode and 0.7 U L-1 for colorimetric mode.

Targeting LINC070974 inhibits lung adenocarcinoma cell proliferation and progression by interacting with Y-box binding protein 1.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Increasing evidence suggests that long noncoding RNAs play crucial roles in lung cancer pathogenesis. We previously identified a novel lncRNA, LINC070974, which is associated with tumor cell proliferation. In the present study, we find that knockdown of LINC070974 inhibits cell proliferation, migration and invasion as well as tumor formation both in vitro and in nude mice. LINC070974 silencing also improves cisplatin efficacy in A549/DDP cells. The function of LINC070974 may depend on its interaction with YBX1. Knockdown of LINC070974 reduces the recruitment of YBX1 to the CCND1 promoter and delays tumor progression through its coregulatory genes, which are mainly involved in the p53 signaling pathway. We utilize nebulized inhalation to deliver siRNAs targeting LINC070974 and find that LINC070974 significantly prevents tumor metastasis and growth in lung tissues. These findings reveal the role of LINC070974 in lung cancer and suggest a promising therapeutic approach involving siRNA inhalation.