miR-143-3p modulates depressive-like behaviors via Lasp1 in the mouse ventral hippocampus.

Depression is a prevalent and intricate mental disorder. The involvement of small RNA molecules, such as microRNAs in the pathogenesis and neuronal mechanisms underlying the depression have been documented. Previous studies have demonstrated the involvement of microRNA-143-3p (miR-143-3p) in the process of fear memory and pathogenesis of ischemia; however, the relationship between miR-143-3p and depression remains poorly understood. Here we utilized two kinds of mouse models to investigate the role of miR-143-3p in the pathogenesis of depression. Our findings reveal that the expression of miR-143-3p is upregulated in the ventral hippocampus (VH) of mice subjected to chronic restraint stress (CRS) or acute Lipopolysaccharide (LPS) treatment. Inhibiting the expression of miR-143-3p in the VH effectively alleviates depressive-like behaviors in CRS and LPS-treated mice. Furthermore, we identify Lasp1 as one of the downstream target genes regulated by miR-143-3p. The miR-143-3p/Lasp1 axis primarily affects the occurrence of depressive-like behaviors in mice by modulating synapse numbers in the VH. Finally, miR-143-3p/Lasp1-induced F-actin change is responsible for the synaptic number variations in the VH. In conclusion, this study enhances our understanding of microRNA-mediated depression pathogenesis and provides novel prospects for developing therapeutic approaches for this intractable mood disorder.

Development and validation of a nomogram for screening patients with type 2 diabetic ketoacidosis.

OBJECTIVE AND BACKGROUND: The early detection of diabetic ketoacidosis (DKA) in patients with type 2 diabetes (T2D) plays a crucial role in enhancing outcomes. We developed a nomogram prediction model for screening DKA in T2D patients. At the same time, the input variables were adjusted to reduce misdiagnosis. METHODS: We obtained data on T2D patients from Mimic-IV V0.4 and Mimic-III V1.4 databases. A nomogram model was developed using the training data set, internally validated, subjected to sensitivity analysis, and further externally validated with data from T2D patients in Aviation General Hospital. RESULTS: Based on the established model, we analyzed 1885 type 2 diabetes patients, among whom 614 with DKA. We further additionally identified risk factors for DKA based on literature reports and multivariate analysis. We identified age, glucose, chloride, calcium, and urea nitrogen as predictors in our model. The logistic regression model demonstrated an area under the curve (AUC) of 0.86 (95%CI: 0.85-0.90]. To validate the model, we collected data from 91 T2D patients, including 15 with DKA, at our hospital. The external validation of the model yielded an AUC of 0.68 (95%CI: 0.67-0.70). The calibration plot confirmed that our model was adequate for predicting patients with DKA. The decision-curve analysis revealed that our model offered net benefits for clinical use. CONCLUSIONS: Our model offers a convenient and accurate tool for predicting whether DKA is present. Excluding input variables that may potentially hinder patient compliance increases the practical application significance of our model.

Nanotopography Influences Host-Pathogen Quorum Sensing and Facilitates Selection of Bioactive Metabolites in Mesenchymal Stromal Cells and Pseudomonas aeruginosa Co-Cultures.

Orthopedic implant-related bacterial infections and resultant antibiotic-resistant biofilms hinder implant-tissue integration and failure. Biofilm quorum sensing (QS) communication determines the pathogen colonization success. However, it remains unclear how implant modifications and host cells are influenced by, or influence, QS. High aspect ratio nanotopographies have shown to reduce biofilm formation of Pseudomonas aeruginosa, a sepsis causing pathogen with well-defined QS molecules. Producing such nanotopographies in relevant orthopedic materials (i.e., titanium) allows for probing QS using mass spectrometry-based metabolomics. However, nanotopographies can reduce host cell adhesion and regeneration. Therefore, we developed a polymer (poly(ethyl acrylate), PEA) coating that organizes extracellular matrix proteins, promoting bioactivity to host cells such as human mesenchymal stromal cells (hMSCs), maintaining biofilm reduction. This allowed us to investigate how hMSCs, after winning the race for the surface against pathogenic cells, interact with the biofilm. Our approach revealed that nanotopographies reduced major virulence pathways, such as LasR. The enhanced hMSCs support provided by the coated nanotopographies was shown to suppress virulence pathways and biofilm formation. Finally, we selected bioactive metabolites and demonstrated that these could be used as adjuncts to the nanostructured surfaces to reduce biofilm formation and enhance hMSC activity. These surfaces make excellent models to study hMSC-pathogen interactions and could be envisaged for use in novel orthopedic implants.

Micromechanical modelling for bending behaviour of novel bioinspired alumina-based dental composites.

The clinical failure mode of dental crown ceramics involves radial cracking at the interface, driven by the surface tension generated from the flexure of the ceramic layer on the subsurface. This results in a reduced lifespan for most all-ceramic dental crowns. Therefore, investigating optimal material combinations to reduce stress concentration in dental crown materials has become crucial for future successful clinical applications. The anisotropic complex structures of natural materials, such as nacre, could potentially create suitable strong and damage-resistant materials. Their imitation of natural structural optimisation and mechanical functionality at both the macro- and micro-levels minimises weaknesses in dental crowns. This research aims to optimise cost-effective, freeze-casted bioinspired composites for the manufacture of novel, strong, and tough ceramic-based dental crowns. To this end, multilayer alumina (Al2O3) composites with four different polymer phases were tested to evaluate their bending behaviour and determine their flexural strength. A computational model was developed and validated against the experimental results. This model includes Al2O3 layers that undergo gentle compression and distribute stress, while the polymer layers act as stress relievers, undergoing plastic deformation to reduce stress concentration. Based on the experimental data and numerical modelling, it was concluded that these composites exhibit variability in mechanical properties, primarily due to differences in microstructures and their flexural strength. Furthermore, the findings suggest that bioinspired Al2O3-based composites demonstrate promising deformation and strengthening behaviour, indicating potential for application in the dental field.

Disulfiram/copper complex improves the effectiveness of the WEE1 inhibitor Adavosertib in p53 deficient non-small cell lung cancer via ferroptosis.

Cancer cells lacking functional p53 exhibit poor prognosis, necessitating effective treatment strategies. Inhibiting WEE1, the G2/M cell cycle checkpoint gatekeeper, represents a promising approach for treating p53-deficient NSCLC. Here, we investigate the connection between p53 and WEE1, as well as explore a synergistic therapeutic approach for managing p53-deficient NSCLC. Our study reveals that p53 deficiency upregulates both protein levels and kinase activity of WEE1 by inhibiting its SUMOylation process, thereby enhancing the susceptibility of p53-deficient NSCLC to WEE1 inhibitors. Furthermore, we demonstrate that the WEE1 inhibitor Adavosertib induces intracellular lipid peroxidation, specifically in p53-deficient NSCLC cells, suggesting potential synergy with pro-oxidant reagents. Repurposing Disulfiram (DSF), an alcoholism medication used in combination with copper (Cu), exhibits pro-oxidant properties against NSCLC. The levels of WEE1 protein in p53-deficient NSCLC cells treated with DSF-Cu exhibit a time-dependent increase. Subsequent evaluation of the combination therapy involving Adavosertib and DSF-Cu reveals reduced cell viability along with smaller tumor volumes and lighter tumor weights observed in both p53-deficient cells and xenograft models while correlating with solute carrier family 7-member 11 (SLC7A11)/glutathione-regulated ferroptosis pathway activation. In conclusion, our findings elucidate the molecular interplay between p53 and WEE1 and unveil a novel synergistic therapeutic strategy for treating p53-deficient NSCLC.

Unveiling the effects of environmental factors and Yellow River inputs on the ichthyoplankton community structure in typical bays.

To unravel the effects of environmental factors on fishery resources in the bay, we conducted six biological and environmental surveys in the Laizhou Bay between 2013 and 2020. The findings of our study illuminated several key aspects: (1) The annual discharge of water and sediment from the Yellow River to Laizhou Bay exhibited notable variations, while concurrently, environmental factors including temperature, salinity, and suspended particle matter underwent fluctuations, yet remained within a relatively stable range overall. (2) A total of 8318 eggs and larvae belonging to 10 orders, 16 families, and 19 genera were collected. Significant interannual fluctuations had been documented in the species composition, abundance, and biodiversity of ichthyoplankton. Notably, both Shannon-Wiener diversity index and Pielou evenness index were significantly negatively correlated with suspended particle matter concentration. (3) The water and sediment discharge significantly positively correlated with the number of cold-temperature species. However, the sediment input negatively correlated with the number of continental shelf benthopelagic fish. (4) Redundancy and correlation analyses confirmed the strong link between spatial and temporal distribution of fish communities and environmental factors, with salinity and dissolved oxygen key for ichthyoplankton abundance. Our research offers a scientific foundation for targeted fishery protection and management, which is crucial for preserving the ecological functions of spawning grounds in the bay.

Robust Nitrogen-Doped Microporous Carbon via Crown Ether-Functionalized Benzoxazine-Linked Porous Organic Polymers for Enhanced CO2 Adsorption and Supercapacitor Applications.

Nitrogen-doped carbon materials, characterized by abundant microporous and nitrogen functionalities, exhibit significant potential for carbon dioxide capture and supercapacitors. In this study, a class of porous organic polymer (POP) were successfully synthesized by linking Cr-TPA-4BZ-Br4 and tetraethynylpyrene (Py-T). The model benzoxazine monomers of Cr-TPA-4BZ and Cr-TPA-4BZ-Br4 were synthesized using the traditional three-step method [involving CH═N formation, reduction by NaBH4, and Mannich condensation]. Subsequently, the Sonogashira coupling reaction connected the Cr-TPA-4BZ-Br4 and Py-T monomers, forming Cr-TPA-4BZ-Py-POP. The successful synthesis of Cr-TPA-4BZ-Br4 and Cr-TPA-4BZ-Py-POP was confirmed through various analytical techniques. After verifying the successful synthesis of Cr-TPA-4BZ-Py-POP, carbonization and KOH activation procedures were conducted. These crucial steps led to the formation of poly(Cr-TPA-4BZ-Py-POP)-800, a carbon material with a structure akin to graphite. In practical applications, poly(Cr-TPA-4BZ-Py-POP)-800 exhibited a noteworthy CO2 adsorption capacity of 4.4 mmol/g, along with specific capacitance values of 397.2 and 159.2 F g-1 at 0.5 A g-1 (measured in a three-electrode cell) and 1 A g-1 (measured in a symmetric coin cell), respectively. These exceptional dual capabilities stem from the optimal ratio of heteroatom doping. The outstanding performance of poly(Cr-TPA-4BZ-Py-POP)-800 microporous carbon holds significant promise for addressing contemporary energy and environmental challenges, making substantial contributions to both sectors.

Left atrial strain parameters to predicting elevated left atrial pressure in patients with atrial fibrillation.

OBJECTIVES: To assess the ability of left atrial (LA) strain parameters to discriminate patients with elevated left atrial pressure (LAP) from patients with atrial fibrillation (AF). METHODS AND RESULTS: A total of 142 patients with non-valvular AF who underwent first catheter ablation (CA) between November 2022 and November 2023 were enrolled in the study. Conventional and speckle-tracking echocardiography (STE) were performed in all patients within 24 h before CA, and LAP was invasively measured during the ablation procedure. According to mean LAP, the study population was classified into two groups of normal LAP (LAP < 15 mmHg, n = 101) and elevated LAP (LAP ≥ 15 mmHg, n = 41). Compared with the normal LAP group, elevated LAP group showed significantly reduced LA reservoir strain (LASr) [9.14 (7.97-11.80) vs. 20 (13.59-26.96), p < .001], and increased LA filling index [9.60 (7.15-12.20) vs. 3.72 (2.17-5.82), p < .001], LA stiffness index [1.13 (.82-1.46) vs. .47 (.30-.70), p < .001]. LASr, LA filling index and LA stiffness index were independent predictors of elevated LAP after adjusted by the type of AF, EDT, E/e', mitral E, and peak acceleration rate of mitral E velocity. The receiver-operating characteristic curve (ROC) analysis showed LA strain parameters (area under curve [AUC] .794-.819) could provide similar or greater diagnostic accuracy for elevated LAP, as compared to conventional echocardiographic parameters. Furthermore, the novel algorithms built by LASr, LA stiffness index, LA filling index, and left atrial emptying fraction (LAEF), was used to discriminate elevated LAP in AF with good accuracy (AUC .880, accuracy of 81.69%, sensitivity of 80.49%, and specificity of 82.18%), and much better than 2016 ASE/EACVI algorithms in AF. CONCLUSION: In patients with AF, LA strain parameters could be useful to predict elevated LAP and non-inferior to conventional echocardiographic parameters. Besides, the novel algorithm built by LA strain parameters combined with conventional parameters would improve the diagnostic efficiency.

Terahertz Spectra of Mannitol and Erythritol: A Joint Experimental and Computational Study.

Sugar substitutes, which generally refer to a class of food additives, mostly have vibration frequencies within the terahertz (THz) band. Therefore, THz technology can be used to analyze their molecular properties. To understand the characteristics of sugar substitutes, this study selected mannitol and erythritol as representatives. Firstly, PXRD and Raman techniques were used to determine the crystal structure and purity of mannitol and erythritol. Then, the THz time-domain spectroscopy (THz-TDS) system was employed to measure the spectral properties of the two sugar substitutes. Additionally, density functional theory (DFT) was utilized to simulate the crystal configurations of mannitol and erythritol. The experimental results showed good agreement with the simulation results. Finally, microfluidic chip technology was used to measure the THz spectroscopic properties of the two sugar substitutes in solution. A comparison was made between their solid state and aqueous solution state, revealing a strong correlation between the THz spectra of the two sugar substitutes in both states. Additionally, it was found that the THz spectrum of a substance in solution is related to its concentration. This study provides a reference for the analysis of sugar substitutes.

Exosome-loaded hyaluronic acid hydrogel composite with oxygen-producing 3D printed polylactic acid scaffolds for bone tissue repair and regeneration.

Bone defects can interfere with bone healing by disrupting the local environment, resulting in vascular damage and hypoxia. Under these conditions, insufficient oxygen availability is a significant factor that exacerbates disease by blocking angiogenesis or osteogenesis. Exosomes play a crucial role in intercellular communication and modulation of inflammation to aid bone regeneration. However, the distance between exosomes and areas of damage can hinder efficient bone generation and cell survival. To overcome this limitation, we fabricated a continuous oxygen-supplying composite scaffold, with the encapsulation of calcium peroxide in a polylactic acid three-dimensional (3D) printing construct (CPS), as both an oxygen source and hydroxyapatite (HAP) precursor. Furthermore, bone marrow mesenchymal stem cell (BMSC)-derived exosomes were incorporated into hyaluronic acid (HA) hydrogels to stimulate cell growth and modulate inflammation. The release of exosomes into cells leads to an increase in alkaline phosphatase production. In vivo results demonstrated that the composite scaffold regulated the inflammatory microenvironment, relieved tissue hypoxia, and promoted new bone formation. These results indicate that the synergistic effect of exosomes and oxygen promoted the proliferation of BMSCs, alleviated inflammation and exhibited excellent osteogenic properties. In conclusion, this osteogenic functional composite scaffold material offers a highly effective approach for bone repair.

G-MBRMD: Lightweight liver segmentation model based on guided teaching with multi-head boundary reconstruction mapping distillation.

BACKGROUND AND OBJECTIVES: Liver segmentation is pivotal for the quantitative analysis of liver cancer. Although current deep learning methods have garnered remarkable achievements for medical image segmentation, they come with high computational costs, significantly limiting their practical application in the medical field. Therefore, the development of an efficient and lightweight liver segmentation model becomes particularly important. METHODS: In our paper, we propose a real-time, lightweight liver segmentation model named G-MBRMD. Specifically, we employ a Transformer-based complex model as the teacher and a convolution-based lightweight model as the student. By introducing proposed multi-head mapping and boundary reconstruction strategies during the knowledge distillation process, Our method effectively guides the student model to gradually comprehend and master the global boundary processing capabilities of the complex teacher model, significantly enhancing the student model's segmentation performance without adding any computational complexity. RESULTS: On the LITS dataset, we conducted rigorous comparative and ablation experiments, four key metrics were used for evaluation, including model size, inference speed, Dice coefficient, and HD95. Compared to other methods, our proposed model achieved an average Dice coefficient of 90.14±16.78%, with only 0.6 MB memory and 0.095 s inference speed for a single image on a standard CPU. Importantly, this approach improved the average Dice coefficient of the baseline student model by 1.64% without increasing computational complexity. CONCLUSION: The results demonstrate that our method successfully realizes the unification of segmentation precision and lightness, and greatly enhances its potential for widespread application in practical settings.

Highly integrated automatic injection terahertz microfluidic biosensor based on metasurface and LT-GaAs photoconductive antenna.

In this paper, a highly integrated terahertz (THz) biosensor is proposed and implemented, which pioneered the preparation of low-temperature gallium arsenide (LT-GaAs) thin film photoconductive antenna (PCA) on the sensor for direct generation and detection of THz waves, simplifying complex terahertz time-domain spectroscopy (THz-TDS) systems. A latch type metasurface is deposited in the detection region to produce a resonance absorption peak at 0.6 THz that is independent of polarisation. Microfluidics is utilised and automatic injection is incorporated to mitigate the experimental effects of hydrogen bond absorption of THz waves in aqueous-based environment. Additionally, cell damage is minimised by regulating the cell flow rate. The biosensor was utilised to detect the concentration of three distinct sizes of bacteria with successful results. The assay was executed as a proof of concept to detect two distinct types of breast cancer cells. Based on the experimental findings, it has been observed that the amplitude and blueshift of the resonance absorption peaks have the ability to identify and differentiate various cancer cell types. The findings of this study introduce a novel approach for developing microfluidic THz metasurface biosensors that possess exceptional levels of integration, sensitivity, and rapid label-free detection capabilities.

Trehalose and its dihydrate: terahertz insights from solid to solution states.

Carbohydrates are pivotal biomolecules in biochemistry; this study employs terahertz time-domain spectroscopy (THz-TDS) to investigate the spectral characteristics of trehalose and its hydrate across the 0.1 to 2.2 THz frequency range. Notable differences in spectra between the two compounds were observed. Density Functional Theory (DFT) simulations of the crystal structure were conducted to elucidate this phenomenon. The consistency between experimental results and simulations substantiates the reliability of the experimental findings. Additionally, the spectral characteristics of these carbohydrates in solution were examined using microfluidic chip technology. This approach facilitates a comprehensive comparison of their behaviors in both solid and solution states.

Resveratrol targeting NRF2 disrupts the binding between KEAP1 and NRF2-DLG motif to ameliorate oxidative stress damage in mice pulmonary infection.

ETHNOPHARMACOLOGICAL RELEVANCE: The root of Polygonum cuspidatum Sieb. et Zucc (PC), known as 'Huzhang' in the Chinese Pharmacopoeia, has been traditionally employed for its anti-inflammatory, antiviral, antimicrobial, and other biological activities. Polydatin (PD) and its aglycone, resveratrol (RES), are key pharmacologically active components responsible for exerting anti-inflammatory and antioxidant effects. However, its specific targets and action mechanisms remain unclear. AIM OF THE STUDY: The equilibrium of the KEAP1-NRF2 system serves as the primary protective response to oxidative and electrophilic stresses within the body, particularly in cases of acute lung injury caused by pathogenic microbial infection. In this study, the precise mechanisms by which RES alleviates oxidative stress damage in conjunction with NRF2 activators are discussed. MATERIALS AND METHODS: The active components from PC were screened to evaluate their potential to inhibit reactive oxygen species (ROS) and activate antioxidant activity dependent on antioxidant response elements (ARE). RES was evaluated for its potential to alleviate the oxidative stress caused by pathogenic microbial infection. Functional probes were designed to study the RES distribution and identify its targets. A lipopolysaccharide (LPS)-induced oxidative injury model was used to evaluate the effects of RES on the KEAP1-NRF2/ARE pathway in RAW 264.7 cells. The interaction between RES and NRF2 was elucidated using drug-affinity responsive target stability (DARTS), cellular thermal shift assays (CETSA), co-immunoprecipitation (Co-IP), and microscale thermophoresis (MST) techniques. The key binding sites were predicted using molecular docking and validated in NRF2-knockdownand reconstructed cells. Finally, protective effects against pulmonary stress were verified in a mouse model of pathogenic infection. RESULTS: The accumulation of RES in lung macrophages disrupted the binding between KEAP1 and NRF2, thereby preventing the ubiquitination degradation of NRF2 through its interaction with Ile28 on the NRF2-DLG motif. The activation of NRF2 resulted in the upregulation of nuclear transcription, enhances the expression of antioxidant genes dependent on ARE, suppresses ROS generation, and ameliorates oxidative damage both in vivo and in vitro. CONCLUSION: These findings shed light on the potential of RES to mitigate oxidative stress damage caused by pathogenic microorganism-induced lung infections and facilitate the discovery of novel small molecule modulators targeting the KEAP1-NRF2 DLG motif interaction.

Melatonin alleviates endoplasmic reticulum stress to improve ovarian function by regulating the mTOR pathway in aged laying hens.

Granular cell apoptosis is a key factor leading to follicular atresia and decreased laying rate in aged laying hens. Endoplasmic reticulum stress (ERS) induced cell apoptosis is a new type of apoptosis pathway. Previous studies have shown that the ERS pathway is involved in the regulation of follicular development and atresia, and can be regulated by mTOR. Melatonin (MEL) can protect the normal development of follicles, but the precise mechanism by which MEL regulates follicular development is not yet clear. So, we investigated the potential relationship between MEL and ERS and mTOR signaling pathway in vivo through intraperitoneal injection of MEL in aged laying hens. The results show that the laying rate, ovarian follicle number, plasma MEL, E2, LH, FSH concentrations, as well as the mRNA expression of mTOR signaling-associated genes TSC1, TSC2, mTOR, 4E-BP1, and S6K in old later-period chicken control (Old-CN) group was significantly decreased (P < 0.01). In contrast, the ERS-related of plasma and granular cell layer mRNA expression of Grp78, CHOP, and Caspase-3 was significantly increased (P < 0.01). While both of the effects were reversed by MEL. Then, aging granulosa cells were treated with MEL in vitro, followed by RNA seq analysis, and it was found that 259 and 322 genes were upregulated and downregulated. After performing GO enrichment analysis, it was found that DEGs significantly contribute to the biological processes including cell growth and apoptosis. Using pathway enrichment analysis, we found significant overrepresentation of cellular processes related to mTOR signaling and endoplasmic reticulum (ER) stress, involving genes such as GRB10, SGK1, PRKCA, RPS6KA2, RAF1, PIK3R3, FOXO1, DERL3, HMOX1, TLR7, VAMP7 and INSIG2. The obtained results of RT-PCR showed consistency with the RNA-Seq data. In summary, the underlined results revealed that MEL has significantly contributed to follicular development via activating the mTOR signaling pathway-related genes and alleviating ERS-related genes in laying hens. The current study provides a theoretical background for enhancing the egg-laying capability of hens and also providing a basis for elucidating the molecular mechanism of follicular selection.

Melatonin alleviates endoplasmic reticulum stress and follicular granulosa cell apoptosis by regulating ATF4 to activate mTOR signaling pathway in chickens.

Follicular atresia in chickens reduces the number of follicles that can further develop, leading to decrease egg laying. Endoplasmic reticulum stress (ERS) can initiate a unique pathway inducing the apoptosis of follicular granulosa cells, thus reducing egg laying. Melatonin (MEL) is involved in the regulation of follicle development, ovulation, and oocyte maturation, and is closely related to follicle fate. Mammalian target of Rapamycin (mTOR) signaling pathway plays an important role in cell growth regulation, and that there is a possible crosstalk between melatonin and mTOR activity in granular cells maturation and ovulation. This study aimed to investigate whether MEL inhibits ERS and follicular granulosa cell apoptosis by regulating ATF4 to activate mTOR signaling pathway in chickens. Frist, we established an in vitro ERS cell model using tunicamycin (TM). The results showed that different concentrations of TM exhibited dose-dependent inhibition of cell activity and induction of granulosa cells (P<0.01). Therefore, we chose 5 µg/mL of TM and a treatment time for 6 h as the optimal concentration for the following experiments. Then we investigate whether melatonin can inhibit ERS. TM treatment decreased the cell viability and Bcl-2 expression, increasing ROS levels and the mRNA expression of Grp78, ATF4, CHOP, PERK, eIF-2α, and BAX (P<0.01), whereas TM+MEL treatment significantly inhibited these changes (P<0.01). Then we explored whether melatonin protects follicular granulosa cells from ERS-induced apoptosis through the mammalian target of rapamycin (mTOR) signaling pathway by regulating ATF4, we found that ATF4 knockdown inhibited ERS by decreasing the expression of ERS-related genes and proteins and activating mTOR signaling pathway by increasing the protein expression of p4E-BP1 and pT389-S6K (P<0.001), while these changes were promoted by TM+si-ATF4+MEL treatment (P<0.01). These results indicate that MEL could alleviate TM-induced ERS by regulating ATF4 to activate mTOR signaling pathway in follicular granulosa cells, thus providing a new perspective for prolonging the laying cycle in chickens.

Mechanotransducive surfaces for enhanced cell osteogenesis, a review.

Novel strategies employing mechano-transducing materials eliciting biological outcomes have recently emerged for controlling cellular behaviour. Targeted cellular responses are achieved by manipulating physical, chemical, or biochemical modification of material properties. Advances in techniques such as nanopatterning, chemical modification, biochemical molecule embedding, force-tuneable materials, and artificial extracellular matrices are helping understand cellular mechanotransduction. Collectively, these strategies manipulate cellular sensing and regulate signalling cascades including focal adhesions, YAP-TAZ transcription factors, and multiple osteogenic pathways. In this minireview, we are providing a summary of the influence that these materials, particularly titanium-based orthopaedic materials, have on cells. We also highlight recent complementary methodological developments including, but not limited to, the use of metabolomics for identification of active biomolecules that drive cellular differentiation.

Oridonin promotes RSL3-induced ferroptosis in breast cancer cells by regulating the oxidative stress signaling pathway JNK/Nrf2/HO-1.

The incidence and mortality of breast cancer, the most common malignant tumor among women in the world, are increasing year by year, which greatly threatens women's health. Ferroptosis is an iron and lipid reactive oxygen species (ROS)-dependent process, a novel form of cell death that is distinct from apoptosis and is closely related to the progression of breast cancer. Inducing the occurrence of ferroptosis in tumor cells can effectively block its malignant progress in vivo. Oridonin (ORI), the primary active ingredient extracted from the Chinese herbal medicine Rabdosia rubescens, has been shown to cause glutathione depletion and directly inhibit glutathione peroxidase 4 induced cell death by ferroptosis, but its mechanism of action in breast cancer remains inadequately elucidated. Therefore, we further investigated whether ORI could promote RSL3-induced ferroptosis in breast cancer cells by regulating the oxidative stress pathway JNK/Nrf2/HO-1. In our study, we assessed cell survival of RSL3 and ORI treatment by MTT assay, and found that co-treatment with RSL3 and ORI inhibited cell proliferation, as evidenced by the cloning assay. To investigate the ability of ORI to promote RSL3-induced ferroptosis in breast cancer cells, we measured levels of ROS, malondialdehyde, glutathione, superoxide dismutase, and Fe2+ content. Lipid peroxidation, ROS, and mitochondrial membrane potential levels induced by co-treatment of ORI with RSL3 were reversed by ferrostatin-1, further confirming that the cell death induced by RSL3 and ORI was ferroptosis rather than other programmed cell death modes. Moreover, RSL3 and ORI co-treatment regulated the JNK/Nrf2/HO-1 axis, as demonstrated by western blotting and target activator validation. Our results showed that ORI could enhance the inhibitory effect of RSL3 on breast cancer cells viability via the induction of ferroptosis. Mechanistically, it potentiated RSL3-induced ferroptosis in breast cancer cells by activating the JNK/Nrf2/HO-1 axis. This study provides a theoretical basis for the application of ORI based on the mechanism of ferroptosis, and provides potential natural drug candidates for cancer prevention and treatment.

PROTAC EZH2 degrader-1 overcomes the resistance of podophyllotoxin derivatives in refractory small cell lung cancer with leptomeningeal metastasis.

BACKGROUND: Leptomeningeal metastasis (LM) of small cell lung cancer (SCLC) is a highly detrimental occurrence associated with severe neurological disorders, lacking effective treatment currently. Proteolysis-targeting chimeric molecules (PROTACs) may provide new therapeutic avenues for treatment of podophyllotoxin derivatives-resistant SCLC with LM, warranting further exploration. METHODS: The SCLC cell line H128 expressing luciferase were mutated by MNNG to generate H128-Mut cell line. After subcutaneous inoculation of H128-Mut into nude mice, H128-LM and H128-BPM (brain parenchymal metastasis) cell lines were primarily cultured from LM and BPM tissues individually, and employed to in vitro drug testing. The SCLC-LM mouse model was established by inoculating H128-LM into nude mice via carotid artery and subjected to in vivo drug testing. RNA-seq and immunoblotting were conducted to uncover the molecular targets for LM. RESULTS: The SCLC-LM mouse model was successfully established, confirmed by in vivo live imaging and histological examination. The upregulated genes included EZH2, SLC44A4, VEGFA, etc. in both BPM and LM cells, while SLC44A4 was particularly upregulated in LM cells. When combined with PROTAC EZH2 degrader-1, the drug sensitivity of cisplatin, etoposide (VP16), and teniposide (VM26) for H128-LM was significantly increased in vitro. The in vivo drug trials with SCLC-LM mouse model demonstrated that PROTAC EZH2 degrader-1 plus VM26 or cisplatin/ VP16 inhibited H128-LM tumour significantly compared to VM26 or cisplatin/ VP16 alone (P < 0.01). CONCLUSION: The SCLC-LM model effectively simulates the pathophysiological process of SCLC metastasis to the leptomeninges. PROTAC EZH2 degrader-1 overcomes chemoresistance in SCLC, suggesting its potential therapeutic value for SCLC LM.

Diallyl disulfide antagonizes DJ-1 mediated proliferation, epithelial-mesenchymal transition, and chemoresistance in gastric cancer cells.

Diallyl disulfide (DADS), an organic component of allicin abstracted from garlic, possesses multi-target antitumor activity. DJ-1 performs a vital function in promoting AKT aberrant activation via down-regulating phosphatase and tensin homologue (PTEN) in tumors. It is unknown the involvement of DJ-1 in epithelial-mesenchymal transition (EMT) of gastric cancer (GC) cells. The purpose of this study is to investigate whether diallyl disulfide (DADS) intervenes in the role of DJ-1 in GC. Based on the identification that the correlation between high DJ-1 and low PTEN expression in GC was implicated in clinical progression, we illuminated that down-regulation of DJ-1 by DADS aided in an increase in PTEN expression and a decrease in phosphorylated AKT levels, which was in line with the results manifested in the DJ-1 knockdown and overexpressed cells, concurrently inhibiting proliferation, EMT, migration, and invasion. Furthermore, the antagonistic effects of DADS on DJ-1 were observed in in vivo experiments. Additionally, DADS mitigated the DJ-1-associated drug resistance. The current study revealed that DJ-1 is one of potential targets for DADS, which hopefully provides a promising strategy for prevention and adjuvant chemotherapy of GC.