Niraparib Enhances and Synergizes with Ganglioside GD2 to Potentiate its Inhibitory Effect on Bladder Cancer Cells.

PURPOSE: This study aimed to study the inhibitory effect of niraparib alone or in combination with GD2 specific antibody on Bladder Cancer (BCa). METHODS: The migration ability of BCa cells was assessed through a scratch assay. CCK-8 assay was performed to evaluate the viability of BCa cells, and Transwell invasion assays were utilized to examine invasive capacity. The expression levels of E-cadherin and vimentin in BCa cells were measured using QRT-PCR. RESULTS: Western blot showed the EMT level to be the lowest in the niraparib+GD2 group. The transwell invasion assay suggested that the invasion ability of BCa cells was weakened in the niraparib+ GD2 group. CCK8 assay indicated that the proliferation ability of BCa cells was decreased. Scratch test suggested that the migration ability of BCa cells was weakened. PCR result showed that the niraparib + GD2 group had the most significant inhibitory effect on mRNA expression of EMT markers. CONCLUSION: Niraparib combined with a GD2-specific antibody exerted a more prominent inhibitory effect on BCa.

Xiangshao Granules Ameliorate Post-Stroke Depression by Inhibiting Activation of Microglia and IDO1 Expression in Hippocampus and Prefrontal Cortex.

OBJECTIVE: To investigate the therapeutic effect of Xiangshao Granules (XSG) on post-stroke depression (PSD) and explore the underlying mechanisms. METHODS: Forty-three C57BL/6J mice were divided into 3 groups: sham (n=15), PSD+vehicle (n=14), and PSD+XSG (n=14) groups according to a random number table. The PSD models were constructed using chronic unpredictable mild stress (CUMS) after middle cerebral artery occlusion (MCAO). The sham group only experienced the same surgical operation, but without MACO and CUMS stimulation. The XSG group received XSG (60 mg/kg per day) by gavage for 4 weeks. The mice in the sham and vehicle groups were given the same volume of 0.9% saline at the same time. The body weight and behavior tests including open field test, sucrose preference test, tail suspension test, and elevated plus-maze test, were used to validate the PSD mouse model. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining were used to evaluate the anti-inflammatory effects of XSG. The potential molecular mechanisms were explored and verified through network pharmacology analysis, Nissl staining, Western blot, ELISA, and RT-qPCR, respectively. RESULTS: The body weight and behavior tests showed that MCAO combined with CUMS successfully established the PSD models. XSG alleviated neuronal damage, reduced the expressions of pro-apoptotic proteins Caspase-3 and B-cell lymphoma-2 (BCL-2)-associated X (BAX), and increased the expression of anti-apoptotic protein BCL-2 in PSD mice (P<0.05 or P<0.01). XSG inhibited microglial activation and the expressions of pro-inflammatory cytokines including tumor necrosis factor-α, interleukin (IL)-1 ß, and IL-6 via the toll-like receptor 4/nuclear factor kappa-B signaling pathway in PSD mice (P<0.05 or P<0.01). Furthermore, XSG decreased the expression of indoleamine 2,3-dioxygenase1 (IDO1) and increased the concentration of 5-hydroxytryptamine in PSD mice (P<0.05 or P<0.01). CONCLUSION: XSG could reverse the anxiety/depressionlike behaviors and reduce the neuronal injury in the hippocampus and prefrontal cortex of PSD mice, which may be a potential therapeutic agent for PSD.

Metabolic mediators: microbial-derived metabolites as key regulators of anti-tumor immunity, immunotherapy, and chemotherapy.

The human microbiome has recently emerged as a focal point in cancer research, specifically in anti-tumor immunity, immunotherapy, and chemotherapy. This review explores microbial-derived metabolites, emphasizing their crucial roles in shaping fundamental aspects of cancer treatment. Metabolites such as short-chain fatty acids (SCFAs), Trimethylamine N-Oxide (TMAO), and Tryptophan Metabolites take the spotlight, underscoring their diverse origins and functions and their profound impact on the host immune system. The focus is on SCFAs' remarkable ability to modulate immune responses, reduce inflammation, and enhance anti-tumor immunity within the intricate tumor microenvironment (TME). The review critically evaluates TMAO, intricately tied to dietary choices and gut microbiota composition, assessing its implications for cancer susceptibility, progression, and immunosuppression. Additionally, the involvement of tryptophan and other amino acid metabolites in shaping immune responses is discussed, highlighting their influence on immune checkpoints, immunosuppression, and immunotherapy effectiveness. The examination extends to their dynamic interaction with chemotherapy, emphasizing the potential of microbial-derived metabolites to alter treatment protocols and optimize outcomes for cancer patients. A comprehensive understanding of their role in cancer therapy is attained by exploring their impacts on drug metabolism, therapeutic responses, and resistance development. In conclusion, this review underscores the pivotal contributions of microbial-derived metabolites in regulating anti-tumor immunity, immunotherapy responses, and chemotherapy outcomes. By illuminating the intricate interactions between these metabolites and cancer therapy, the article enhances our understanding of cancer biology, paving the way for the development of more effective treatment options in the ongoing battle against cancer.

Cuproptosis: Mechanisms, biological significance, and advances in disease treatment-A systematic review.

BACKGROUND: Copper is an essential trace element for biological systems, as it plays a critical role in the activity of various enzymes and metabolic processes. However, the dysregulation of copper homeostasis is closely associated with the onset and progression of numerous diseases. In recent years, copper-induced cell death, a novel form of cellular demise, has garnered significant attention. This process is characterized by the abnormal accumulation of intracellular copper ions, leading to cellular dysfunction and eventual cell death. Copper toxicity occurs through the interaction of copper with acylated enzymes in the tricarboxylic acid (TCA) cycle. This interaction results in subsequent protein aggregation, causing proteotoxic stress and ultimately resulting in cell death. Despite the promise of these findings, the detailed mechanisms and broader implications of cuproptosis remain underexplored. Therefore, our study aimed to investigate the role of copper in cell death and autophagy, focusing on the molecular mechanisms of cuproptosis. We also aimed to discuss recent advancements in copper-related research across various diseases and tumors, providing insights for future studies and potential therapeutic applications. MAIN BODY: This review delves into the biological significance of copper metabolism and the molecular mechanisms underlying copper-induced cell death. Furthermore, we discuss the role of copper toxicity in the pathogenesis of various diseases, emphasizing recent advancements in the field of oncology. Additionally, we explore the therapeutic potential of targeting copper toxicity. CONCLUSION: The study highlights the need for further research to explore alternative pathways of copper-induced cell death, detailed mechanisms of cuproptosis, and biomarkers for copper poisoning. Future research should focus on exploring the molecular mechanisms of cuproptosis, developing new therapeutic strategies, and verifying their safety and efficacy in clinical trials.

Targeting proliferating cell nuclear antigen enhances ionizing radiation-induced cytotoxicity in prostate cancer cells.

BACKGROUND: Proliferating cell nuclear antigen (PCNA) is essential for DNA replication and repair, cell growth, and survival. PCNA also enhances androgen receptor (AR) signaling in prostate cancer (PC) cells. We identified a PCNA interaction protein (PIP) box at the N-terminal domain of AR and developed a small peptide PCNA inhibitor R9-AR-PIP containing AR PIP-box. We also identified a series of small molecule PCNA inhibitors (PCNA-Is) that bind directly to PCNA and interrupt PCNA functions. The present study investigated the effects of the PCNA inhibitors on the sensitivity of PC cells to X-ray radiation. METHODS: The effects of targeting PCNA on radio sensitivity of PC cells were investigated in four lines of castration-resistant PC (CRPC) cells with different AR expression statuses. The cells were treated with the PCNA inhibitors and X-ray radiation alone or in combination. The effects of the treatment on expression of AR target genes, DNA damage response, DNA damage, homologous recombination repair (HRR), and cytotoxicity were evaluated. RESULTS: We found that the androgen response element (ARE) occupancy of the DNA damage response gene PARP1 by AR is significantly attenuated by PCNA-I1S or R9-AR-PIP combined with X-ray radiation, while X-ray radiation alone does not enhance the ARE occupancy. PCNA-I1S or R9-AR-PIP alone significantly inhibits occupancy of the AR-occupied regions (AROR) in PRKDC and XRCC2 genes. R9-AR-PIP and PCNA-I1S inhibit expression of AR-Vs target gene cyclin A2 and show the additive effects with radiation in AR-positive CRPC cells. Targeting PCNA by PCNA-I1S and R9-AR-PIP downregulates expression of DNA damage response genes EXO1, Rad54L, Rad51, and/or PARP1 and shows the additive effects with radiation as compared with their respective controls in AR-positive CRPC LNCaP-AI, 22Rv1, and R1-D567 cells, but not in AR-negative PC-3 cells. R9-AR-PIP and PCNA-I1S elevate the levels of phospho-DNA-PKcs(S2056) and γH2AX, indicating DNA damage in response to radiation in AR-positive cells. The HRR is significantly attenuated by PCNA inhibitors PCNA-I1S, R9-AR-PIP, and T2AA in all four CRPC cells examined, and inhibited by Enzalutamide (Enz) only in 22RV1 cells. The cytotoxicity induced by X-ray radiation in androgen-dependent LNCaP cells is enhanced by Enz and a lower concentration of R9-AR-PIP in the colony formation assay. R9-AR-PIP at higher concentration reduces the colony formation and has an additive effect with X-ray radiation in all AR expressing cells, regardless of AR-FL and AR-Vs, but does not significantly alter the colony formation in AR-negative PC-3 cells. PCNA-I1S attenuates colony formation and has an additive effect with ionizing radiation in all four CRPC cells, regardless of AR expression status. CONCLUSION: These data provide a strong rationale for the therapy studies using PCNA-I1S or R9-AR-PIP in combination with X-ray radiation against CRPC tumors in preclinical models.

Perfusion deficit and vessel wall characteristics to predict recurrent ischemic events in medically treated patients with chronic symptomatic anterior circulation large vessel occlusion.

BACKGROUND: To investigate the association between perfusion deficit, vessel wall characteristics, and risk of recurrent ischemic events in medically treated patients with chronic symptomatic anterior circulation large vessel occlusion. METHODS: We retrospectively reviewed chronic symptomatic patients due to anterior circulation large vessel occlusion in our center. All patients received multiparametric magnetic resonance imaging (including perfusion-weighted imaging and high-resolution vessel wall imaging) within 4 weeks to 3 months after symptom onset. The association between baseline clinical or imaging variables and recurrent ischemic events was assessed in bivariate models and multivariable logistic regression to identify independent predictors of recurrence. RESULTS: Among 71 enrolled patients, 21.1% (15/71) patients had recurrent ischemic events (nine ischemic strokes and six transient ischemic attacks) during a 2-year follow-up. In bivariate models, hypertension, occlusion with hyperintense signals, the presence of intraluminal thrombus, Tmax >4 s volume, Tmax >6 s volume, Tmax >8 s volume, and Tmax >10 s volume were associated with recurrence (all p < 0.05). In multivariate analysis, hypertension (p = 0.039, OR 10.057 (95% CI, 1.123-90.048)), higher deficit volume of Tmax >4 s (p = 0.011, OR 1.012 (95% CI, 1.003-1.021)) and occlusion with hyperintense signal (p = 0.030, OR 6.732 (95% CI, 1.200-37.772)) were still independent predictors of recurrent ischemic events. CONCLUSIONS: Besides hypertension history, higher deficit volume of Tmax >4 s and occlusion with hyperintense signal determined using multiparametric MRI are strongly associated with risk for recurrent ischemic events in medically treated patients with chronic symptomatic anterior circulation large vessel occlusion. Future studies are needed to determine the utility of revascularization strategies in such high-risk patients.

Lactylation signature identifies liver fibrosis phenotypes and traces fibrotic progression to hepatocellular carcinoma.

Introduction: Precise staging and classification of liver fibrosis are crucial for the hierarchy management of patients. The roles of lactylation are newly found in the progression of liver fibrosis. This study is committed to investigating the signature genes with histone lactylation and their connection with immune infiltration among liver fibrosis with different phenotypes. Methods: Firstly, a total of 629 upregulated and 261 downregulated genes were screened out of 3 datasets of patients with liver fibrosis from the GEO database and functional analysis confirmed that these differentially expressed genes (DEGs) participated profoundly in fibrosis-related processes. After intersecting with previously reported lactylation-related genes, 12 DEGs related to histone lactylation were found and narrowed down to 6 core genes using R algorithms, namely S100A6, HMGN4, IFI16, LDHB, S100A4, and VIM. The core DEGs were incorporated into the Least absolute shrinkage and selection operator (LASSO) model to test their power to distinguish the fibrotic stage. Results: Advanced fibrosis presented a pattern of immune infiltration different from mild fibrosis, and the core DEGs were significantly correlated with immunocytes. Gene set and enrichment analysis (GSEA) results revealed that core DEGs were closely linked to immune response and chemokine signaling. Samples were classified into 3 clusters using the LASSO model, followed by gene set variation analysis (GSVA), which indicated that liver fibrosis can be divided into status featuring lipid metabolism reprogramming, immunity immersing, and intermediate of both. The regulatory networks of the core genes shared several transcription factors, and certain core DEGs also presented dysregulation in other liver fibrosis and idiopathic pulmonary fibrosis (IPF) cohorts, indicating that lactylation may exert comparable functions in various fibrotic pathology. Lastly, core DEGs also exhibited upregulation in HCC. Discussion: Lactylation extensively participates in the pathological progression and immune infiltration of fibrosis. Lactylation and related immune infiltration could be a worthy focus for the investigation of HCC developed from liver fibrosis.

Impact of Family Doctor Contract Services on Preventable Hospitalizations Amongst Patients with Hypertension in Rural China: Mediating Role of Primary Healthcare Quality.

Purpose: The objective of this study was to explore the connection between family doctor contract services and preventable hospitalizations. Additionally, we sought to examine the role of primary health care quality as a mediating factor in the link between family doctor contract services and preventable hospitalizations among patients with hypertension. Patients and Methods: This cross-sectional study was performed in Dangyang (Hubei Province, Central China) and Xishui (Guizhou Province, Western China) counties in July-August 2023. Participants comprised 625 patients selected via a multi-stage sampling method. Causal mediation analysis was conducted to explore the effect of family doctor contract services on preventable hospitalizations and the mediating effect of primary healthcare quality on this relationship. Results: Utilization rate of family doctor contract services of hypertensive patients was 58.6%, score of primary health service quality was 70.75 and incidence of preventable hospitalizations was 28.2%. Amongst hypertensive patients, utilization of family doctor contract services decreased the occurrence of preventable hospitalizations, with a total effect of -0.22 (p < 0.001). Primary healthcare quality mediates the association, with a mediate effect of -0.05 (p < 0.001), explaining 22.73% of the total effect. Conclusion: Improving the utilization of family doctor contract services and primary healthcare quality may result in lower rates of preventable hospitalizations amongst hypertensive patients.

Icing and Adhesion Behaviors on Surfaces with Varied Lattice Constants.

Investigating droplet wetting and icing behavior is crucial for comprehending the principles of surface icing and the design of anti-icing surfaces. In this study, we present the evidence from molecular dynamics (MD) simulations that reveal a hitherto unreported behavior of droplet wetting and icing adhesion on surfaces with lattice constants from 2.7 to 4.5 Å. Here, we observe that the contact angles (CA) of droplets on a face-centered cubic (FCC) lattice surface consistently correlate positively with the lattice constant. Further examination of droplet behavior on an idealized crystal surface reveals that hydrophilic surfaces (e.g., CA = 85°) inhibit freezing more effectively than hydrophobic surfaces (e.g., CA = 97°). This finding contradicts the conventional explanation that hydrophobic surfaces reduce heterogeneous nucleation, thereby delaying icing. This study introduces a mechanistic explanation for the promotion of water icing by hydrophobic surfaces and offers a novel design concept for the development of anti-ice surfaces in future applications.

Hydrogen sulfide upregulates SIRT1 to inhibit ox-HDL-induced endothelial cell damage and mitochondrial dysfunction.

BACKGROUND: Under normal circumstances, high-density lipoprotein (HDL) is considered to have cardiovascular protective effects, but the impact of oxidized HDL (ox-HDL) on vascular endothelial function remains poorly understood. Mitochondrial function is closely related to endothelial function, and hydrogen sulfide (H2S) is a gas with endothelial protective properties. The novel hydrogen sulfide donor AP39 can target mitochondria to release H2S, but the combined effects of ox-HDL and AP39 on vascular endothelium are not well studied. METHODS: We established a cell model of ox-HDL-induced endothelial cell damage and mitochondrial dysfunction using human umbilical vein endothelial cells (HUVECs) and conducted AP39 pretreatment. The experiments confirmed the functional damage and mitochondrial dysfunction in HUVECs caused by ox-HDL. Additionally, to further explore the role of SIRT1 in AS, we analyzed SIRT1 expression in AS carotid artery tissue. This included the analysis of differentially expressed genes from AS-related datasets, presented through volcano plots and heatmaps, with enrichment analysis of downregulated genes in KEGG pathways and GO functions. Furthermore, we evaluated the differences in SIRT1 expression in coronary arteries with varying degrees of stenosis and in early and late-stage AS carotid artery tissues, and analyzed data from SIRT1 knockout mouse models. RESULTS: The experimental results indicate that AP39 effectively alleviated ox-HDL-induced endothelial cell damage and mitochondrial dysfunction by upregulating SIRT1 expression. MTT and CCK-8 assays showed that ox-HDL treatment led to decreased cell viability and proliferation in HUVECs, reduced eNOS expression, and significantly increased levels of ICAM-1, IL-6, and TNF-α, along with enhanced monocyte adhesion. These findings reveal the damaging effects of ox-HDL on HUVECs. Transcriptomic data indicated that while SIRT1 expression did not significantly differ in coronary arteries with varying degrees of stenosis, it was notably downregulated in AS carotid artery tissues, especially in late-stage AS tissues. KEGG pathway enrichment analysis revealed that SIRT1 downregulated genes were associated with processes such as vascular smooth muscle contraction, while GO analysis showed that these downregulated genes were involved in muscle system processes and muscle contraction functions, further confirming SIRT1's critical role in AS pathology. In transcriptomic data from the SIRT1 knockout mouse model, elevated levels of inflammation-related proteins IL-6 and TNF-α were observed after SIRT1 knockout, along with decreased expression of the chaperone protein PGC-1α. The expression of mitochondrial-related functional proteins Nrf2 and PGC-1α was positively correlated with SIRT1 expression, while inflammation-related proteins ICAM-1, IL-6, IL-20, and TNF-α were negatively correlated with SIRT1 expression. We further discovered that ox-HDL triggered mitochondrial dysfunction, as evidenced by reduced expression of Mfn2, Nrf2, PGC1-α, UCP-1, and SIRT1, corroborating the results from the previous database analysis. Additionally, mitochondrial dysfunction was characterized by decreased mitochondrial membrane potential (MMP), increased mitochondrial ROS levels, and reduced ATP content, further impacting cellular energy metabolism and respiratory function. Subsequent experimental results showed that the addition of AP39 mitigated these adverse effects, as evidenced by decreased levels of ICAM-1, IL-6, and TNF-α, increased eNOS expression, reduced monocyte adhesion, increased mitochondrial H2S content, and upregulated expression of SIRT1 protein associated with mitochondrial function, reduced ROS levels, and increased ATP content. Furthermore, validation experiments using the SIRT1 inhibitor EX527 confirmed that AP39 alleviated ox-HDL-induced endothelial cell damage and mitochondrial dysfunction by upregulating SIRT1 expression. CONCLUSION: Ox-HDL can induce damage and mitochondrial dysfunction in HUVECs, while AP39 inhibits ox-HDL-induced endothelial cell damage and mitochondrial dysfunction by upregulating SIRT1.

Subgroups of High-Cost Patients and Their Preventable Inpatient Cost in Rural China.

BACKGROUND: High-cost patients account for most healthcare costs and are highly heterogeneous. This study aims to classify high-cost patients into clinically homogeneous subgroups, describe healthcare utilization patterns of subgroups, and identify subgroups with relatively high preventable inpatient cost (PIC) in rural China. METHODS: A population-based retrospective study was performed using claims data in Xi county, Henan province. 32 108 high-cost patients, representing the top 10% of individuals with the highest total spending, were identified. A density-based clustering algorithm combined with expert opinions were used to group high-cost patients. Healthcare utilization (including admissions, length of stay, and outpatient visits) and spending characteristics (including total spending, and the proportion of PIC, inpatient and out-of-pocket spending on total spending) were described among subgroups. PIC was calculated based on potentially preventable hospitalizations (PPHs) which were identified according to the Agency for Healthcare Research and Quality Prevention Quality Indicators algorithm. RESULTS: High-cost patients were more likely to be older (Mean=51.87, SD=22.28), male (49.03%) and from poverty-stricken families (37.67%) than non-high-cost patients, with 2.49 (SD=2.47) admissions and 3.25 (SD=4.52) outpatient visits annually. Fourteen subgroups of high-cost patients were identified: chronic disease, non-trauma diseases which need surgery, female disease, cancer, eye disease, respiratory infection/inflammation, skin disease, fracture, liver disease, vertigo syndrome and cerebral infarction, mental disease, arthritis, renal failure, and other neurological disorders. The annual admissions ranged from 1.83 (SD=1.23, fracture) to 12.21 (SD=9.26, renal failure), and the average length of stay ranged from 6.61 (SD=10.00, eye disease) to 32.11 (SD=28.78, mental disease) days among subgroups. The chronic disease subgroup showed the largest proportion of PIC on total spending (10.57%). CONCLUSION: High-cost patients were classified into 14 clinically distinct subgroups which had different healthcare utilization and spending characteristics. Different targeted strategies may be needed for subgroups to reduce preventable hospitalizations. Priority should be given to high-cost patients with chronic diseases.

Corrigendum: Ginsenoside compound K attenuates ox-LDL-mediated macrophage inflammation and foam cell formation via autophagy induction and modulating NF-kB, p38, and JNK MAPK signaling.

[This corrects the article DOI: 10.3389/fphar.2020.567238.].

The application of rhubarb concoctions in traditional Chinese medicine and its compounds, processing methods, pharmacology, toxicology and clinical research.

Objective: This study reviews the development of rhubarb processing and the current status of pharmacological research. We summarized the effects of different processing methods on the active compounds, pharmacological effects, and toxicity of rhubarb, as well as the clinical application of different concoctions, providing reference for further pharmacological research and clinical application of rhubarb. Methods: A comprehensive literature review was conducted using databases such as Pubmed, Embase, National Science and Technology Library, Web of science, CNKI, China Science and Technology Journal Database, SinoMed, and the Pharmacopoeia of the People's Republic of China. Search terms included "rhubarb", "raw rhubarb", "wine rhubarb", "cooked rhubarb", "rhubarb charcoal", "herbal processing", "compounds", "pharmacological effects", "inflammation", "gastrointestinal bleeding", and "tumor". Results: Historical records of rhubarb processing date back to the Han Dynasty, with continual innovations. Currently, the types of rhubarb used in traditional Chinese medicine have stabilized to three species: Rheum palmatum L., Rheum tanguticum Maxim.ex Balf. and Rheum officinale Baill. Common concoctions include raw rhubarb, wine rhubarb, cooked rhubarb and rhubarb charcoal. The active compounds of rhubarb are known to defecation, exhibit antibacterial and anti-inflammatory properties, regulate coagulation, protect the digestive system, and possess anti-tumor activities. Guided by Chinese medicine theory, the use of different rhubarb concoctions can enhance specific effects such as purgation to eliminate accumulation, clearing heat and toxins, cooling blood to stop hemorrhages, activating blood circulation to remove blood stasis, and inducing dampness to descend jaundice, thereby effectively treating various diseases. The therapeutic impact of these concoctions on diseases reflects not only in the changes to the active compounds of rhubarb but also in the formulations of traditional Chinese medicine. Processing has also shown advantages in reducing toxicity. Conclusion: Different processing methods alter the active compounds of rhubarb, thereby enhancing its various pharmacological effects and meeting the therapeutic needs of diverse diseases. Selecting an appropriate processing method based on the patient's specific conditions can maximize its pharmacological properties and improve clinical outcomes.

Study on co-amorphous emerging solubilization behavior after gelation during dissolution: The importance of complexation and anti-crystallization.

Co-amorphous (CM) is a promising technology for enhancing the aqueous solubility of insoluble drugs, but the gelation phenomenon has often occurred during the dissolution process and seriously threatened their solubility/dissolution performance. Therefore, it's quite important to design favorable CM systems to alleviate or even avoid the adverse effects of gelation phenomenon. In this study, CM systems of taxifolin (TAX) and oxymatrine (OMT) (TAX-OMT CMs) were constructed to improve the solubility and dissolution properties of TAX. Interestingly, TAX-OMT CMs gradually aggregated and obviously gelled during dissolution, but the solubility and dissolution of TAX in TAX-OMT CMs were significantly enhanced compared to crystalline TAX. Consequently, the underlying solubilization mechanisms of TAX-OMT CMs after gelation were systematically explored. For one thing, the complexation between the two components in TAX-OMT CMs was verified by phase solubility, fluorescence spectroscopy and isothermal titration calorimetry. For another, the residual solids of TAX-OMT CMs after dissolution evaluation were thoroughly characterized by means of powder X-ray diffraction, fourier transform infrared spectroscopy, scanning electron microscopy, which showed the anti-crystallization property of TAX-OMT CMs. Furthermore, molecular simulation demonstrated the intermolecular interactions of TAX-OMT CMs alone and TAX-OMT complexes in aqueous solution. Finally, pharmacokinetics study in rats suggested that the bioavailability of TAX in TAX-OMT CM (1:2) was approximately 5.5-fold higher than that of crystalline TAX after oral administration. Collectively, this study reveals the importance of complexation and anti-crystallization effects of CM systems on maintaining solubilization behavior after gelation, providing an effective strategy to improve the absorption performance of pharmaceutical CM systems.

Transgenerational and parental impacts of acrylamide exposure on Caenorhabditis elegans: Physiological, behavioral, and genetic mechanisms.

Acrylamide is pervasive, and its exposure poses numerous health risks. This study examines both the direct and transgenerational effects of acrylamide toxicity in Caenorhabditis elegans, focusing on physiological and behavioral parameters. Parental exposure to acrylamide compromised several aspects of nematode health, including lifespan, reproductive capacity, body dimensions, and motor and sensory functions. Notably, while exposure to low concentrations of acrylamide did not alter the physiological traits of the offspring-except for their learning and memory-these findings suggest a possible adaptive response to low-level exposure that could be inherited by subsequent generations. Furthermore, continued acrylamide exposure in the offspring intensified both physiological and perceptual toxicity. Detailed analysis revealed dose-dependent alterations in acrylamide's detoxification and metabolic pathways. In particular, it inhibits the gene gst-4, which encodes a crucial enzyme in detoxification, mitigates DNA damage induced by acrylamide, and highlights a potential therapeutic target to reduce its deleterious effects.

ORANGE interplays with TCP7 to regulate endoreduplication and leaf size.

Leaf size is a crucial agronomic trait directly affecting crop yield, which is mainly determined by coordinated cell proliferation, growth, and differentiation. Although endoreduplication is known to be correlated with the onset of cell differentiation and leaf size, the underlying molecular mechanisms are largely unclear. The DnaJ-like zinc finger domain-containing protein ORANGE (OR) was initially demonstrated to confer the massive accumulation of carotenoids in cauliflower curds. However, the cauliflower or mutant also possesses other phenotypes such as smaller curds, smaller leaves with elongated petioles, and delayed flowering. Here, we demonstrated that OR physically interacts with the transcription factor TCP7, which promotes endoreduplication by inducing the expression of the cell cycle gene CYCLIN D 1;1 (CYCD1;1). Overexpression of OR resulted in smaller rosette leaves, whereas the OR-silencing plants had larger rosette leaves than wild-type plants. Our microscopic observations and flow cytometry analysis revealed that the variation in leaf size was a result of different endoreduplication levels. Genetic analyses showed that OR functions antagonistically with TCP7 in regulating the endoreduplication levels in leaf cells. While the expression of OR is induced by TCP7, OR represses the transactivation activity of TCP7 by affecting its binding capability to the TCP-binding motif in the promoter region of CYCD1;1. Through this interaction, OR negatively regulates the expression of CYCD1;1 and reduces the nuclear ploidy level in rosette leaf cells. Our findings provide new insights into the regulatory network of leaf size and also reveal a regulatory circuit controlling endoreduplication in leaf cells.

The affective factors of depression symptoms in hypertensive patients and the protective effect of physical activity.

OBJECTIVE: To investigate the potential affective factors of depressive symptoms in patients with hypertension and explore the protective effects of physical activity. METHODS: 211 hypertensive patients aged over 18 years were consecutively recruited. All patients completed a self-designed questionnaire and the Hospital Anxiety and Depression Scale (HADS) to assess the coexistence of depressive symptoms, and psychiatrists were invited to diagnose depression when necessary. Full-night polysomnography was performed to detect the sleep pattern. The association between sleep structure and depressive symptoms was tested by using logistic regression analysis, and contributing factors as well as the effect of physical activity were assessed among patients with and without depressive symptoms. RESULTS: Of the 211 subjects, 33.6% of cases were coexistent with depressive symptoms. Female gender [OR (95%CI): 2.83 (1.44-5.57), P = 0.003) and the greater percentage of REM stage [OR (95%CI): 1.09 (1.01-1.18), P = 0.024] were the risk factors of depressive symptoms, while doing physical activity showed as the protective factor. Patients with REM stage ≥ 20% showed a higher score on HADS-D than those with REM stage < 20% [(4.9 ± 3.8) vs. (3.7 ± 3.1), P = 0.018]. Compared to individuals who never did physical activity, those who did physical activity 1-2 times per week and ≥ 3 times per week had a 52% and 62% risk reduction in depressive symptoms respectively. Patients who did physical activity had lower levels of high-sensitivity C-reactive protein (hs-CRP) compared to those who never did physical activity. CONCLUSION: Female gender and a higher percentage of REM stage are risk factors for depressive symptoms in hypertension, while physical activity may benefit depressive symptoms by reducing serum levels of hs-CRP.

Multiparametric mri-based radiomics nomogram for predicting lymph-vascular space invasion in cervical cancer.

PURPOSE: To develop and validate a multiparametric magnetic resonance imaging (mpMRI)-based radiomics model for predicting lymph-vascular space invasion (LVSI) of cervical cancer (CC). METHODS: The data of 177 CC patients were retrospectively collected and randomly divided into the training cohort (n=123) and testing cohort (n = 54). All patients received preoperative MRI. Feature selection and radiomics model construction were performed using max-relevance and min-redundancy (mRMR) and the least absolute shrinkage and selection operator (LASSO) on the training cohort. The models were established based on the extracted features. The optimal model was selected and combined with clinical independent risk factors to establish the radiomics fusion model and the nomogram. The diagnostic performance of the model was assessed by the area under the curve. RESULTS: Feature selection extracted the thirteen most important features for model construction. These radiomics features and one clinical characteristic were selected showed favorable discrimination between LVSI and non-LVSI groups. The AUCs of the radiomics nomogram and the mpMRI radiomics model were 0.838 and 0.835 in the training cohort, and 0.837 and 0.817 in the testing cohort. CONCLUSION: The nomogram model based on mpMRI radiomics has high diagnostic performance for preoperative prediction of LVSI in patients with CC.

The long non-coding RNA CCAT1 promotes erlotinib resistance in cholangiocarcinoma by inducing epithelial-mesenchymal transition via the miR-181a-5p/ROCK2 axis.

Cholangiocarcinoma (CCA) is a common malignancy of the digestive system, and its treatment is greatly challenged by rising chemoresistance. Long non-coding RNAs (lncRNAs) have been shown to play critical roles in the development of drug resistance in tumors. However, the role of the lncRNA CCAT1 in erlotinib resistance in CCA remains unclear. In this investigation, we identified CCAT1 as a pivotal factor contributing to erlotinib resistance in CCA. Furthermore, we uncovered that lncRNA CCAT1 modulated epithelial-mesenchymal transition (EMT) through Rho-associated coiled-coil-forming protein kinase 2 (ROCK2), thereby conferring erlotinib resistance upon CCA cells. Mechanistically, we demonstrated that miR-181a-5p interacted with CCAT1 to modulate the expression of ROCK2. Collectively, these findings shed light on the significant role of CCAT1 in the development of erlotinib resistance in CCA. The functional suppression of CCAT1 holds promise in enhancing the sensitivity to erlotinib by reversing EMT through the miR-181a-5p/ROCK2 signaling pathway. These findings provide valuable insights into the mechanisms underlying erlotinib resistance in CCA and the potential strategies for its treatment.