Integrated analysis of metabolome, transcriptome, and bioclimatic factors of Acer truncatum seeds reveals key candidate genes related to unsaturated fatty acid biosynthesis, and potentially optimal production area.

BACKGROUND: Lipids found in plant seeds are essential for controlling seed dormancy, dispersal, and defenses against biotic and abiotic stress. Additionally, these lipids provide nutrition and energy and are therefore important to the human diet as edible oils. Acer truncatum, which belongs to the Aceaceae family, is widely cultivated around the world for its ornamental value. Further because its seed oil is rich in unsaturated fatty acids (UFAs)- i.e. α-linolenic acid (ALA) and nervonic acid (NA)- and because it has been validated as a new food resource in China, the importance of A. truncatum has greatly risen. However, it remains unknown how UFAs are biosynthesized during the growth season, to what extent environmental factors impact their content, and what areas are potentially optimal for their production. RESULTS: In this study, transcriptome and metabolome of A. truncatum seeds at three representative developmental stages was used to find the accumulation patterns of all major FAs. Cumulatively, 966 metabolites and 87,343 unigenes were detected; the differential expressed unigenes and metabolites were compared between stages as follows: stage 1 vs. 2, stage 1 vs. 3, and stage 2 vs. 3 seeds, respectively. Moreover, 13 fatty acid desaturases (FADs) and 20 ß-ketoacyl-CoA synthases (KCSs) were identified, among which the expression level of FAD3 (Cluster-7222.41455) and KCS20 (Cluster-7222.40643) were consistent with the metabolic results of ALA and NA, respectively. Upon analysis of the geographical origin-affected diversity from 17 various locations, we found significant variation in phenotypes and UFA content. Notably, in this study we found that 7 bioclimatic variables showed considerable influence on FAs contents in A. truncatum seeds oil, suggesting their significance as critical environmental parameters. Ultimately, we developed a model for potentially ecological suitable regions in China. CONCLUSION: This study provides a comprehensive understanding of the relationship between metabolome and transcriptome in A. truncatum at various developmental stages of seeds and a new strategy to enhance seed FA content, especially ALA and NA. This is particularly significant in meeting the increasing demands for high-quality edible oil for human consumption. The study offers a scientific basis for A. truncatum's novel utilization as a woody vegetable oil rather than an ornamental plant, potentially expanding its cultivation worldwide.

Research status and challenges of plant-derived exosome-like nanoparticles.

In recent years, there has been an increasing number of related studies on exosomes. Most studies have focused on exosomes derived from mammals, confirming the important role that exosomes play in cell communication. Plants, as a natural ingredient, plant-derived exosomes have been confirmed to have similar structures and functions to mammalian-derived exosomes. Plant-derived exosome-like nanoparticles (PELNs) are lipid bilayer membrane nanovesicles containing bioactive constituents such as miRNA, mRNA, protein, and lipids obtained from plant cells, that can participate in intercellular communication and mediate transboundary communication, have high bioavailability and low immunogenicity, are relatively safe, and have been shown to play an important role in maintaining cell homeostasis and preventing, and treating a variety of diseases. In this review, we describe the biogenesis, isolation and purification methods, structural composition, stability, safety, function of PELNs and challenges. The functions of PELNs in anti-inflammatory, antioxidant, antitumor and drug delivery are mainly described, and the status of research on exosome nanoparticles of Chinese herbal medicines is outlined. Overall, we summarized the importance of PELNs and the latest research results in this field and provided a theoretical basis for the future research and clinical application of PELNs.

De-Biased Disentanglement Learning for Pulmonary Embolism Survival Prediction on Multimodal Data.

Health disparities among marginalized populations with lower socioeconomic status significantly impact the fairness and effectiveness of healthcare delivery. The increasing integration of artificial intelligence (AI) into healthcare presents an opportunity to address these inequalities, provided that AI models are free from bias. This paper aims to address the bias challenges by population disparities within healthcare systems, existing in the presentation of and development of algorithms, leading to inequitable medical implementation for conditions such as pulmonary embolism (PE) prognosis. In this study, we explore the diverse bias in healthcare systems, which highlights the demand for a holistic framework to reducing bias by complementary aggregation. By leveraging de-biasing deep survival prediction models, we propose a framework that disentangles identifiable information from images, text reports, and clinical variables to mitigate potential biases within multimodal datasets. Our study offers several advantages over traditional clinical-based survival prediction methods, including richer survival-related characteristics and bias-complementary predicted results. By improving the robustness of survival analysis through this framework, we aim to benefit patients, clinicians, and researchers by enhancing fairness and accuracy in healthcare AI systems.

The Active Ingredient Catalpol in Rehmannia glutinosa Reduces Blood Glucose in Diabetic Rats via the AMPK Pathway.

Background: Type 2 diabetes mellitus (T2DM) poses a huge threat to population health globally, and more drugs need to be explored for treatment. In this study, we investigated the mechanism of active ingredient catalpol in Rehmannia glutinosa on reduces blood glucose in diabetic. Methods: The T2DM model was constructed by intraperitoneal injection of streptozotocin into Sprague-Dawley (SD) rats, which were randomly grouped into diabetes model group, pioglitazone group, Rehmannia glutinosa group, catalpol high-dose group, catalpol low-dose group and normal control group.The intervention was continued for 28 d, and changes in body weight, fasting blood glucose, insulin and lipid levels were observed. Results: Of all the drugs, pioglitazone had the most pronounced hypoglycemic effect, which began to decline after 2 weeks of treatment in the low-dose catalpol group and had no hypoglycemic effect in the high-dose catalpol group. Among them, Rehmannia glutinosa was able to increase serum triglyceride level, and pioglitazone effectively reduced total cholesterol level in rats. The low dose of catalpol decreased the concentration of low-density lipoprotein cholesterol (LDL), while the high dose of catalpol increased the concentration of LDL. Conclusion: As an active ingredient in Rehmannia glutinosa, catalpol has the potential to lower blood glucose and improve blood lipids in diabetes treatment, and its action may be achieved by regulating the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway, which provides a new idea for the development of new diabetes therapeutic approaches.

A breakthrough in phytochemical profiling: ultra-sensitive surface-enhanced Raman spectroscopy platform for detecting bioactive components in medicinal and edible plants.

A perennial challenge in harnessing the rich biological activity of medicinal and edible plants is the accurate identification and sensitive detection of their active compounds. In this study, an innovative, ultra-sensitive detection platform for plant chemical profiling is created using surface-enhanced Raman spectroscopy (SERS) technology. The platform uses silver nanoparticles as the enhancing substrate, excess sodium borohydride prevents substrate oxidation, and methanol enables the tested molecules to be better adsorbed onto the silver nanoparticles. Subsequently, nanoparticle aggregation to form stable "hot spots" is induced by Ca2+, and the Raman signal of the target molecule is strongly enhanced. At the same time, deuterated methanol was used as the internal standard for quantitative determination. The method has excellent reproducibility, RSD ≤ 1.79%, and the enhancement factor of this method for the detection of active ingredients in the medicinal plant Coptis chinensis was 1.24 × 109, with detection limits as low as 3 fM. The platform successfully compared the alkaloid distribution in different parts of Coptis chinensis: root > leaf > stem, and the difference in content between different batches of Coptis chinensis decoction was successfully evaluated. The analytical technology adopted by the platform can speed up the determination of Coptis chinensis and reduce the cost of analysis, not only making better use of these valuable resources but also promoting development and innovation in the food and pharmaceutical industries. This study provides a new method for the development, evaluation, and comprehensive utilization of both medicinal and edible plants. It is expected that this method will be extended to the modern rapid detection of other medicinal and edible plants and will provide technical support for the vigorous development of the medicinal and edible plants industry.

Selenium in plants: A nexus of growth, antioxidants, and phytohormones.

Selenium (Se) is an essential micronutrient for both human and animals. Plants serve as the primary source of Se in the food chain. Se concentration and availability in plants is influenced by soil properties and environmental conditions. Optimal Se levels promote plant growth and enhance stress tolerance, while excessive Se concentration can result in toxicity. Se enhances plants ROS scavenging ability by promoting antioxidant compound synthesis. The ability of Se to maintain redox balance depends upon ROS compounds, stress conditions and Se application rate. Furthermore, Se-dependent antioxidant compound synthesis is critically reliant on plant macro and micro nutritional status. As these nutrients are fundamental for different co-factors and amino acid synthesis. Additionally, phytohormones also interact with Se to promote plant growth. Hence, utilization of phytohormones and modified crop nutrition can improve Se-dependent crop growth and plant stress tolerance. This review aims to explore the assimilation of Se into plant proteins, its intricate effect on plant redox status, and the specific interactions between Se and phytohormones. Furthermore, we highlight the proposed physiological and genetic mechanisms underlying Se-mediated phytohormone-dependent plant growth modulation and identified research opportunities that could contribute to sustainable agricultural production in the future.

Rational Design of Non-Noble Metal Single-Atom Catalysts in Lithium-Sulfur Batteries through First Principles Calculations.

Lithium-sulfur (Li-S) batteries with a high theoretical energy density of 2600 Wh·kg-1 are hindered by challenges such as low S conductivity, the polysulfide shuttle effect, low S reduction conversion rate, and sluggish Li2S oxidation kinetics. Herein, single-atom non-noble metal catalysts (SACs) loaded on two-dimensional (2D) vanadium disulfide (VS2) as the potential host materials for the cathode in Li-S batteries were investigated systematically by using first-principles calculations. Based on the comparisons of structural stability, the ability to immobilize sulfur, electrochemical reactivity, and the kinetics of Li2S oxidation decomposition between these non-noble metal catalysts and noble metal candidates, Nb@VS2 and Ta@VS2 were identified as the potential candidates of SACs with the decomposition energy barriers for Li2S of 0.395 eV (Nb@VS2) and of 0.162 eV (Ta@VS2), respectively. This study also identified an exothermic reaction for Nb@VS2 and the Gibbs free energy of 0.218 eV for Ta@VS2. Furthermore, the adsorption and catalytic mechanisms of the VS2-based SACs in the reactions were elucidated, presenting a universal case demonstrating the use of unconventional graphene-based SACs in Li-S batteries. This study presents a universal surface regulation strategy for transition metal dichalcogenides to enhance their performance as host materials in Li-S batteries.

A review of passive acid mine drainage treatment by PRB and LPB: From design, testing, to construction.

An extensive volume of acid mine drainage (AMD) generated throughout the mining process has been widely regarded as one of the most catastrophic environmental problems. Surface water and groundwater impacted by pollution exhibit extreme low pH values and elevated sulfate and metal/metalloid concentrations, posing a serious threat to the production efficiency of enterprises, domestic water safety, and the ecological health of the basin. Over the recent years, a plethora of techniques has been developed to address the issue of AMD, encompassing nanofiltration membranes, lime neutralization, and carrier-microencapsulation. Nonetheless, these approaches often come with substantial financial implications and exhibit restricted long-term sustainability. Among the array of choices, the permeable reactive barrier (PRB) system emerges as a noteworthy passive remediation method for AMD. Distinguished by its modest construction expenses and enduring stability, this approach proves particularly well-suited for addressing the environmental challenges posed by abandoned mines. This study undertook a comprehensive evaluation of the PRB systems utilized in the remediation of AMD. Furthermore, it introduced the concept of low permeability barrier, derived from the realm of site-contaminated groundwater management. The strategies pertaining to the selection of materials, the physicochemical aspects influencing long-term efficacy, the intricacies of design and construction, as well as the challenges and prospects inherent in barrier technology, are elaborated upon in this discourse.

Integrating clinical data mining, network analysis and experimental validation reveal the anti-inflammatory mechanism of Huangqin Qingre Chubi Capsule in rheumatoid arthritis treatment.

ETHNOPHARMACOLOGICAL RELEVANCE: Huangqin Qingre Chubi Capsule (HQC) is a Chinese medicinal compound used for the treatment of damp-heat pattern rheumatism, guided by the traditional Chinese medicine syndrome differentiation practice. HQC has been used in the clinical treatment of rheumatic diseases for more than 20 years with remarkable efficacy. HQC has been experimentally shown to exert anti-arthritic effects via the Wnt signaling pathway. AIM OF THE STUDY: This study used clinical data mining, network analysis, and in vitro and in vivo tests to investigate the anti-arthritic and possible anti-inflammatory mechanism of HQC. Specifically, emphasis was placed on the function of the hsa_circ_0091,685/EIF4A3/IL-17 axis in the anti-inflammatory process. MATERIALS AND METHODS: A random walk model was used to evaluate the effects of HQC on clinical immune inflammatory marker function in patients with RA. Network analysis was used to predict the potential target genes and pathways of HQC. Hematoxylin & eosin, safranin O-fast green and toluidine blue staining, immunohistochemistry, and transmission electron microscopy were performed to evaluate the anti-arthritic effects of HQC in rat models. Cell Counting Kit-8 assay, quantitative real-time polymerase chain reaction, western blotting, enzyme-linked immunosorbent assay, and RNA pull-down were used to study the anti-proliferation and anti-inflammatory mechanisms of HQC. RESULTS: Patients with RA who underwent HQC treatment showed a significant reduction in inflammatory response levels, according to retrospective clinical study. Network analysis revealed that HQC potentially targeted genes and pathways related to inflammation, especially IL-6, IL-17, TNF-α, IL-23, and IL-17 signaling pathway. Animal experiments showed that HQC inhibits inflammation through the IL-17 signaling pathway in rat models. Cellular experiments showed that HQC-containing serum inhibited the inflammatory response in patients with RA-FLS or RA by blocking hsa_circ_0091,685 and EIF4A3 expression. CONCLUSION: In RA patients, HQC reduces the inflammatory response. The antiproliferative and anti-inflammatory qualities of HQC are responsible for its therapeutic impact. The suppression of the hsa_circ_0091,685/EIF4A3/IL-17 axis was linked to these favorable outcomes.

Relationship between serum phosphorus and mortality in non-dialysis chronic kidney disease patients: evidence from NHANES 2001-2018.

BACKGROUND: Hyperphosphatemia is common in chronic kidney disease (CKD), associated with higher mortality in dialysis patients. Its impact in non-dialysis patients, especially those with preserved kidney function, remains uncertain. METHODS: A prospective cohort study was conducted using data from the National Health and Nutrition Examination Survey (2001-2008). Serum phosphorus was analyzed as a continuous variable, or categorized into three groups: < 3.5 mg/dL, 3.5 to < 4.5 mg/dL, and ≥ 4.5 mg/dL. Cox proportional hazards models were used to analyze the association between phosphorus with all-cause and cardiovascular disease (CVD) mortality, with or without adjustment for age, sex, race, hemoglobin, estimated glomerular filtration rate (eGFR), serum albumin, serum calcium, 25(OH)D, obesity, hypertension, diabetes, and CVD. RESULTS: A total of 7694 participants were included in the analysis, representing 28 million CKD patients in the United States. During mean 92 months of follow up, 2708 all-cause deaths (including 969 CVD deaths) were observed. Per 1 mg/dL increase in phosphorus was associated with a 13% and 24% increased risk of all-cause mortality (hazard ratio [HR], 1.13; 95%CI, 1.02-1.24) and CVD mortality (HR, 1.24; 95%CI, 1.07-1.45), respectively. Compared with the < 3.5 mg/dL, phosphorus ≥ 4.5 mg/dL was associated with a 28% and 57% increased risk of all-cause mortality (HR, 1.28; 95%CI, 1.05-1.55) and CVD mortality (HR, 1.57; 95CI, 1.19-2.08), respectively. In participants with eGFR < 60 ml/min/1.73m2, elevated phosphorus (≥ 4.5 mg/ dL) were significantly associated with increased risk of all-cause mortality (HR, 1.36; 95%CI, 1.07-1.72). No significant association was observed in eGFR ≥ 60 ml/min/1.73m2 group (HR, 1.31; 95%CI, 0.86-1.99). This correlation does not differ significantly between subgroups defined by eGFR level (P for interaction = 0.889). CONCLUSION: Serum phosphorus above 4.5 mg/dL is significantly associated with a 28% and 57% increased risk of all-cause and CVD death in non-dialysis CKD patients, respectively. This relationship still demonstrated in patients with eGFR < 60 ml/min/1.73m2. However, for population with eGFR ≥ 60 ml/min/1.73m2, further verification is needed.

Related Factors of CRKP Infection in Neurosurgery and Comparison of Therapeutic Effects of Tigecycline Versus Polymyxin B for CRKP Infection.

Objective: This paper aimed to identify the factors related to Carbapenem-resistant Klebsiella pneumoniae (CRKP) infection in neurosurgical patients, and to compare the therapeutic effects of tigecycline versus polymyxin B against CRKP infection, so as to provide a reliable reference for neurosurgery in future prevention and treatment of CRKP infection. Methods: One hundred and fifty cases of KPN treated in the neurosurgery department of our hospital from January 1, 2019 to December 31, 2021 were selected, 50 of which were found to be infected with CRKP and the other 100 were detected with carbapenem-sensitive Klebsiella pneumoniae (CSKP) by culture, analysis of factors associated with infection with CRKP. Subsequently, CRKP-infected patients were randomized into a group treated with Ti (group Ti) and a group treated with PB (group PB). The clinical efficacy, bacterial clearance, adverse reactions, and pre- and post-treatment hepatorenal function were comparatively analyzed. Results: Based on the Logistic regression analysis, tracheal intubation (or mechanical ventilation), combination of multiple underlying diseases, presence of impaired consciousness, and use of carbapenem antibiotics are independent risk factors for CRKP infection (P < .05). Ti and PB groups had no evident differences in clinical efficacy and bacterial clearance (P > .05); however, Ti group presented a worse hepatorenal function and a higher incidence of adverse reactions than PB group (P < .05). Conclusions: Tracheal intubation (or mechanical ventilation), multiple underlying diseases, consciousness disturbance, and use of carbapenem antibiotics are related factors affecting CRKP infection in neurosurgical patients. Both Ti and PB have excellent therapeutic efficacy, but the former has more obvious toxicity and side effects.

Systematic Pharmacology and Experimental Validation to Reveal the Alleviation of Astragalus membranaceus Regulating Ferroptosis in Osteoarthritis.

Background: Astragalus membranaceus (AM) shows promise as a therapeutic agent for osteoarthritis (OA), a debilitating condition with high disability rates. OA exacerbation is linked to chondrocyte ferroptosis, yet the precise pharmacological mechanisms of AM remain unclear. Methods: We validated AM's protective efficacy in an anterior cruciate ligament transection (ACLT) mouse model of OA. The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database was utilized to identify AM's active components and their targets. FerrDb (a database for regulators and markers of ferroptosis and ferroptosis-disease associations) pinpointed ferroptosis-related targets, while GeneCards, Online Mendelian Inheritance in Man (OMIM), Pharmacogenomics Knowledgebase (PharmGKB), Therapeutic Target Database (TTD), and DrugBank sourced OA-related genes. Molecular docking analysis further validated these targets. Ultimately, the validation of the results was accomplished through in vitro experiments. Results: AM exhibited anabolic effects and suppressed catabolism in OA chondrocytes. Network pharmacology identified 19 common genes, and molecular docking suggested quercetin, an AM constituent, interacts with key proteins like HO-1 and NRF2 to inhibit chondrocyte ferroptosis. In vitro experiments confirmed AM's ability to modulate the NRF2/HO-1 pathway via quercetin, mitigating chondrocyte ferroptosis. Conclusion: This study elucidates how AM regulates chondrocyte ferroptosis, impacting OA progression, providing a theoretical basis and experimental support for AM's scientific application.

Ononin promotes radiosensitivity in lung cancer by inhibiting HIF-1α/VEGF pathway.

BACKGROUND: In our previous study, we provided evidence that Astragalus mongholicus Bunge(AM) and its extracts possess a protective capability against radiation-induced damage, potentially mediated through the reduction of reactive oxygen species (ROS) and nitric oxide (NO). However, we were pleasantly surprised to discover during our experimentation that AM not only offers protection against radiation damage but also exhibits a radiation sensitization effect. This effect may be attributed to a specific small molecule present in AM known as ononin. Currently, radiation sensitizers are predominantly found in nitrazole drugs and nanomaterials, with no existing reports on the radiation sensitization properties of ononin, nor its underlying mechanism. PURPOSE: This study aims to investigate the sensitization effect of the small molecule ononin derived from AM on lung cancer radiotherapy, elucidating its specific molecular mechanism of action. Additionally, the safety profile of combining astragalus small molecule ononin with radiation therapy will be evaluated. METHODS: The effective concentration of ononin was determined through cell survival experiments, and the impact of ononin combined with varying doses of radiation on lung cancer cells was observed using CCK-8 and cell cloning experiments. The apoptotic effect of ononin combined with radiation on lung cancer cells was assessed using Hochester staining, flow cytometry, and WB assay. Additionally, WB and immunofluorescence analysis were conducted to investigate the influence of ononin on HIF-1α/VEGF pathway. Furthermore, Molecular Dynamics Simulation was employed to validate the targeted binding ability of ononin and HIF-1α. A lung cancer cell line was established to investigate the effects of knockdown and overexpression of HIF-1α. Subsequently, the experiment was repeated using tumor bearing nude mice and C57BL/6 mouse models in an in vivo study. Tumor volume was measured using a vernier caliper, while HE, immunohistochemistry, and immunofluorescence techniques were employed to observe the effects of ononin combined with radiation on tumor morphology, proliferation, and apoptosis. Additionally, Immunofluorescence was employed to examine the impact of ononin on HIF-1α/VEGF pathway in vivo, and its effect on liver function in mice was assessed through biochemistry analysis. RESULTS: At a concentration of 25 µM, ononin did not affect the proliferation of lung epithelial cells but inhibited the survival of lung cancer cells. In vitro experiments demonstrated that the combination of ononin and radiation could effectively inhibit the growth of lung cancer cells, induce apoptosis, and suppress the excessive activation of the Hypoxia inducible factor 1 alpha/Vascular endothelial growth factor pathway. In vivo experiments showed that the combination of ononin and radiation reduced the size and proliferation of lung cancer tumors, promoted cancer cell apoptosis, mitigated abnormal activation of the Hypoxia inducible factor 1 alpha pathway, and protected against liver function damage. CONCLUSION: This study provides evidence that the combination of AM and its small molecule ononin can enhance the sensitivity of lung cancer to radiation. Additionally, it has been observed that this combination can specifically target HIF-1α and exert its effects. Notably, ononin exhibits the unique ability to protect liver function from damage while simultaneously enhancing the tumor-killing effects of radiation, thereby demonstrating a synergistic and detoxifying role in tumor radiotherapy. These findings contribute to the establishment of a solid basis for the development of novel radiation sensitizers derived from traditional Chinese medicine.

Structural and biofunctional diversity of sulfated polysaccharides from the genus Codium (Bryopsidales, Chlorophyta): A review.

It is believed that polysaccharides will become a focal point for future production of food, pharmaceuticals, and materials due to their ubiquitous and renewable nature, as well as their exceptional properties that have been extensively validated in the fields of nutrition, healthcare, and materials. Sulfated polysaccharides derived from seaweed sources have attracted considerable attention owing to their distinctive structures and properties. The genus Codium, represented by the species C. fragile, holds significance as a vital economic green seaweed and serves as a traditional Chinese medicinal herb. To date, the cell walls of the genus Codium have been found to contain at least four types of sulfated polysaccharides, specifically pyruvylated ß-d-galactan sulfates, sulfated arabinogalactans, sulfated ß-l-arabinans, and sulfated ß-d-mannans. These sulfated polysaccharides exhibit diverse biofunctions, including anticoagulant, immune-enhancing, anticancer, antioxidant activities, and drug-carrying capacity. This review explores the structural and biofunctional diversity of sulfated polysaccharides derived from the genus Codium. Additionally, in addressing the impending challenges within the industrialization of these polysaccharides, encompassing concerns regarding scale-up production and quality control, we outline potential strategies to address these challenges from the perspectives of raw materials, extraction processes, purification technologies, and methods for quality control.

A naturally derived small molecule compound suppresses tumor growth and metastasis in mice by relieving p53-dependent repression of CDK2/Rb signaling and the Snail-driven EMT.

The tumor suppressor protein p53 is central to cancer biology, with its pathway reactivation emerging as a promising therapeutic strategy in oncology. This study introduced LZ22, a novel compound that selectively inhibits the growth, migration, and metastasis of tumor cells expressing wild-type p53, demonstrating ineffectiveness in cells devoid of p53 or those expressing mutant p53. LZ22's mechanism of action involves a high-affinity interaction with the histidine-96 pocket of the MDM2 protein. This interaction disrupted the MDM2-p53 binding, consequently stabilizing p53 by shielding it from proteasomal degradation. LZ22 impeded cell cycle progression and diminished cell proliferation by reinstating the p53-dependent suppression of the CDK2/Rb signaling pathway. Moreover, LZ22 alleviated the p53-dependent repression of Snail transcription factor expression and its consequent EMT, effectively reducing tumor cell migration and distal metastasis. Importantly, LZ22 administration in tumor-bearing mice did not manifest notable side effects. The findings position LZ22 as a structurally unique reactivator of p53, offering therapeutic promise for the management of human cancers with wild-type TP53.

Traditional Chinese Medicine is Associated with the Reduction in Endpoint Events in Patients with Gouty Arthritis: Cohort Study and Association Rule Analysis.

Objective: This study aimed to evaluate the effect of traditional Chinese medicine (TCM) on endpoint events in patients with gouty arthritis (GA). Methods and Materials: A total of 2091 hospitalized GA patients were followed up by telephone, and propensity score matching (PSM) was used to reduce potential bias in the study design. Cox proportional risk model and Kaplan-Meier survival curve were utilized to analyze the impact and time effect of factors on the readmission of GA patients. The differences of laboratory indexes before and after treatment between the low and high exposure groups were compared, and the types and frequencies of medicines in all patients were counted. Association rule analysis was performed to investigate the association between TCM and test indexes or endpoint events. Results: After 1:1 PSM, 187 patients were enrolled in the TCM group and 187 patients in the non-TCM group. The incidence of readmission, new tophus, and all-cause death was lower in the TCM group than that in the non-TCM group (P < 0.05). Cox proportional risk regression analysis showed that TCM, NSAIDs and uric acid lowering drug were independent protective factors for GA readmission. The protective effect was enhanced by the prolongation of TCM treatment and the drug combinations. Kaplan-Meier survival curves indicated a significantly lower readmission rate in the high exposure group than in the low exposure group (P < 0.01). Compared with before treatment, NLR, hs-CRP, UA, TC and other laboratory indexes of the low and high exposure groups were improved after treatment (P < 0.01); The improvement of TG and TC in the high exposure group was more significant than the low exposure group (P < 0.01). The analysis of medicines used by all patients identified the top 20 Chinese herbal medicines and the top 2 Chinese patent medicines. The core drugs identified through association rule analysis that can improve test index and reduce the incidence of endpoint events include Yiyiren, Danshen, and HQC, among others. The network diagram of association rule analysis intuitively shows the relationship between core drugs and "improvement of indicators" and "the absence of endpoint events". Conclusion: TCM is associated with a reduced incidence of endpoint events in patients with GA.

Complete Restoration of Hearing Loss and Cochlear Synaptopathy via Minimally Invasive, Single-Dose, and Controllable Middle Ear Delivery of Brain-Derived Neurotrophic Factor-Poly(dl-lactic acid-co-glycolic acid)-Loaded Hydrogel.

Noise-induced hearing loss (NIHL) often accompanies cochlear synaptopathy, which can be potentially reversed to restore hearing. However, there has been little success in achieving complete recovery of sensorineural deafness using nearly noninvasive middle ear drug delivery before. Here, we present a study demonstrating the efficacy of a middle ear delivery system employing brain-derived neurotrophic factor (BDNF)-poly-(dl-lactic acid-co-glycolic acid) (PLGA)-loaded hydrogel in reversing synaptopathy and restoring hearing function in a mouse model with NIHL. The mouse model achieved using the single noise exposure (NE, 115 dBL, 4 h) exhibited an average 20 dBL elevation of hearing thresholds with intact cochlear hair cells but a loss of ribbon synapses as the primary cause of hearing impairment. We developed a BDNF-PLGA-loaded thermosensitive hydrogel, which was administered via a single controllable injection into the tympanic cavity of noise-exposed mice, allowing its presence in the middle ear for a duration of 2 weeks. This intervention resulted in complete restoration of NIHL at frequencies of click, 4, 8, 16, and 32 kHz. Moreover, the cochlear ribbon synapses exhibited significant recovery, whereas other cochlear components (hair cells and auditory nerves) remained unchanged. Additionally, the cochlea of NE treated mice revealed activation of tropomyosin receptor kinase B (TRKB) signaling upon exposure to BDNF. These findings demonstrate a controllable and minimally invasive therapeutic approach that utilizes a BDNF-PLGA-loaded hydrogel to restore NIHL by specifically repairing cochlear synaptopathy. This tailored middle ear delivery system holds great promise for achieving ideal clinical outcomes in the treatment of NIHL and cochlear synaptopathy.

Quemeiteng granule relieves goiter by suppressing thyroid microvascular endothelial cell proliferation and angiogenesis via miR-217-5p-mediated targeting of FGF2-induced regulation of the ERK pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Goiters are enlargements of the thyroid gland and are a global public issue. Quemeiteng granule (QMTG) is a traditional Chinese medicine (TCM) formula used to treat goiter in Yunnan Province. However, the effectiveness and underlying mechanism of these treatments have not been fully elucidated. AIM OF THE STUDY: This study aimed to investigate the therapeutic effects of QMTG on goiter and the downstream regulatory mechanisms. MATERIALS AND METHODS: In this study, we first evaluated the antigoiter efficacy of QMTG through biochemical indices [body weight, thyroid coefficient, triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH)] and hematoxylin-eosin (HE) staining in a Propylthiouracil (PTU)-induced model. Based on microRNA sequencing (miRNA-seq) and bioinformatics analysis, key miRNA was screened out. A dual-luciferase reporter assay was performed to confirm the transcriptional regulation of the target gene by the miRNA. The viability of rat thyroid microvascular endothelial cells (RTMECs) and human thyroid microvascular endothelial cells (HTMECs) was assessed using the CCK-8 assays. The migration and angiogenesis of RTMECs and HTMECs were visualized through tube formation and wound scratch assays. Proteins involved in angiogenesis and the ERK pathway were assessed via Western blotting. RESULTS: QMTG significantly increased body weight, decreased the thyroid coefficient, increased the levels of T3, T4, FT3 and FT4 and reduced TSH levels in rats with goiter. QMTG also promoted the morphological recovery of thyroid follicles. MiR-217-5p was identified as a key miRNA. Our studies revealed that miR-217-5p directly targets FGF2 and that QMTG promotes the recovery of thyroid hormone (TH) levels and morphological changes in the thyroid, suppresses thyroid microvascular endothelial cell vitality, tube formation and migration, and reduces the expression of VEGF, Ang-1 and VCAM-1 triggered by miR-217-5p, thereby inhibiting the Ras/MEK/ERK cascade through FGF2. CONCLUSIONS: Our experiments demonstrated that the QMTG had therapeutic effects on goiter. These effects were attributed to the inhibition of ERK pathway-induced proliferation and angiogenesis through the targeting of FGF2 by miR-217-5p.

Triacanthine enhances the sensitivity of colorectal cancer cells to 5-fluorouracil by regulating RRM2.

BACKGROUND: According to the literatures, triacanthine is isolated from the leaves of Gleditsia triacanthos L. and acts as an anti-hypertensive agent, also cardiotonic, antispasmodic and a respiratory analeptic. The 5-fluorouracil (5-FU) is widely used to treat the patients of colorectal cancer (CRC), but the resistance to 5-FU treatment restricts the therapeutic efficacy of CRC patients. PURPOSE: This study aims to explore a novel therapeutics regimen overcoming CRC resistance to 5-FU. METHODS: The cell proliferation of CRC cells was determined by SRB and colony formation assay. Transwell and wound-healing assay were applied to explore the potential metastatic abilities of CRC cells. qRT-PCR and Western blot were performed to evaluate the level of indicated mRNAs and proteins respectively. Xenograft assay was used to explore the anti-CRC effect of triacanthine. RESULTS: Triacanthine statistically restrained CRC proliferation both in vitro and in vivo. Triacanthine induced cell cycle G1/G0 phase arrest in CRC cells. Meanwhile, triacanthine also inhibited the migrative and invasive abilities of CRC cells. A Venn diagram was generated showing that O-6-Methylguanine-DNA Methyltransferase (MGMT) might be a molecular target of triacanthine in treating CRC. Furthermore, triacanthine plus 5-FU significantly suppressed the cell proliferation of CRC cells compared with single agent treatment alone, and highly synergistic anti-cancer effects were scored when 5-FU was combined with triacanthine in CRC cells. In addition, triacanthine sensitized the anti-cancer activity of 5-FU via regulating Ribonucleotide Reductase Regulatory Subunit M2 (RRM2). MGMT or RRM2 might be novel biomarkers for evaluating the therapeutical efficiency of 5-FU in CRC patients. CONCLUSION: We firstly demonstrated triacanthine suppressed cell proliferation and metastasis abilities and found the novel molecular targets of triacanthine in CRC cells. This is the first study to evaluate the anti-cancer efficiency of triacanthine plus 5-FU. Our study has revealed triacanthine as a pertinent sensitizer to 5-FU, and provided novel strategies for predicting outcomes and reversing resistance of 5-FU therapy.