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As the most abundant natural flavonoid in rattan tea, dihydromyricetin (DMY) has shown a wide range of pharmacological effects. In addition to the general characteristics of flavonoids, DMY has the effects of cardioprotection, anti-diabetes, hepatoprotection, neuroprotection, anti-tumor, and dermatoprotection. DMY was also applied for the treatment of bacterial infection, osteoporosis, asthma, kidney injury, nephrotoxicity and so on. These effects to some extent enrich the understanding about the role of DMY in disease prevention and therapy. However, to date, we still have no outlined knowledge about the detailed mechanism of DMY, which might be related to anti-oxidation and anti-inflammation. And the detailed mechanisms may be associated with several different molecules involved in cellular apoptosis, oxidative stress, and inflammation, such as AMP-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), protein kinase B (Akt), nuclear factor-κB (NF-κB), nuclear factor E2-related factor 2 (Nrf2), ATP-binding cassette transporter A1 (ABCA1), peroxisome proliferator-activated receptor-γ (PPARγ) and so on. Here, we summarized the current pharmacological developments of DMY as well as possible mechanisms, aiming to push the understanding about the protective role of DMY as well as its preclinical assessment of novel application.

Background Chemotherapy resistance remains a barrier to improving the prognosis of epithelial ovarian cancer (EOC). ALKBH5 has recently been shown to be one of the RNA N6-methyladenosine (m6A) demethyltransferases associated with various cancers, but its role in cancer therapeutic resistance remains unclear. This study aimed to investigate the role of AlkB homolog 5 (ALKBH5) in cisplatin-resistant EOC. Methods Functional assays were performed both in vitro and in vivo. RNA sequencing (RNA-seq), m6A-modified RNA immunoprecipitation sequencing (MeRIP-seq), chromatin immunoprecipitation, RNA immunoprecipitation, and luciferase reporter and actinomycin-D assays were performed to investigate RNA/RNA interaction and m6A modification of the ALKBH5-HOXA10 loop. Results ALKBH5 was upregulated in cisplatin-resistant EOC and promoted cancer cell cisplatin resistance both in vivo and in vitro. Notably, HOXA10 formed a loop with ALKBH5 and was found to be the upstream transcription factor of ALKBH5. HOXA10 overexpression also facilitated EOC cell chemoresistance both in vivo and in vitro. Collective results of MeRIP-seq and RNA-seq showed that JAK2 is the m6A-modified gene targeted by ALKBH5. The JAK2/STAT3 signaling pathway was activated by overexpression of the ALKBH5-HOXA10 loop, resulting in EOC chemoresistance. Cell sensitivity to cisplatin was rescued by ALKBH5 and HOXA10 knockdown or inhibition of the JAK2/STAT3 signaling pathway in EOC cells overexpressing ALKBH5-HOXA10. Conclusions The ALKBH5-HOXA10 loop jointly activates the JAK2/STAT3 signaling pathway by mediating JAK2 m6A demethylation, promoting EOC resistance to cisplatin. Thus, inhibition of the expression of the ALKBH5-HOXA10 loop may be a potential strategy to overcome cisplatin resistance in EOC.

Background The administration of a boost dose to residual cervical lymph nodes (RCLN) following radiotherapy for nasopharyngeal carcinoma (NPC) remains a controversial contentious issue. This study explored the prognosis of NPC patients with such residuals and evaluated the impact of an intensity-modulated radiotherapy (IMRT) boost on outcome. Methods Two thousand six hundred thirty-three NPC patients following radical IMRT were retrospectively conducted. Clinical data of 1057 NPC patients with RCLN after radical IMRT were analyzed and 199 patients received boost radiation. To balance possible confounders between groups, propensity score matching (PSM) was carried out (ratio: 1:2). Risk classification was according to postradiotherapy Epstein-Barr virus (EBV) DNA and N category. Results Patients with positive RCLN findings exhibited considerably lower 3-year relapse-free survival (RRFS), overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS) rates compared to those with negative findings (98.0% vs. 92.8%; 93.5% vs. 85.0%; 87.0% vs. 68.4%; 92.8% vs. 81.9%, all P  < 0.001). Multivariate analysis indicated that N category and postradiotherapy EBV DNA levels as high-risk factors for RCLN. In the matched cohort, the boost radiation group showed improved 3-year OS (89.4% vs. 80.0%, P  < 0.001), RRFS (95.0% vs. 89.8%, P  = 0.019), PFS (73.8% vs. 63.7%, P  = 0.004), and DMFS (85.2% vs. 74.2%, P  = 0.001). Multivariate analysis confirmed boost radiation as a critical protective prognostic factor. Conclusion For NPC patients with RCLN, adding a boost dosage following radical IMRT results in desirable tumor control and a positive clinical outcome. Individuals with detectable EBV DNA and N2-3 category may benefit from the boost radiation.

AimsWhile nafamostat mesylate (NM) and sodium citrate serve as commonly used extracorporeal anticoagulants in clinical practice, the characteristics and potential risks of their adverse events (AEs) need to be systematically evaluated. This study comparatively analyzed the reporting characteristics of the AEs of the above-mentioned two drugs based on the World Health Organization Adverse Drug Reaction Reporting Database (WHO-VigiAccess), to identify their safety signals and provide evidence-based guidance for optimizing their clinical uses.MethodsMining of the global AE reporting data of NM and sodium citrate was conducted using the WHO-VigiAccess database, with the data collected until 29 December 2024. Statistical analysis was performed using the Reporting Odds Ratio (ROR), the Proportional Reporting Ratio (PRR), the Bayesian Confidence Propagation Neural Network (BCPNN), and the Empirical Bayes Geometric Mean (EBGM). The signal strengths of the AEs of the two drugs at the system organ class and preferred term levels were systematically evaluated in combination with the standardized coding MedDRA.ResultsThis study included 1,572 NM-related reports (59 AEs) and 485 sodium citrate-related reports (102 AEs). NM AEs were mainly concentrated in immune system diseases (23.80%), skin and subcutaneous tissue diseases (16.25%), and gastrointestinal diseases (10.10%), with strong disproportionality signals observed for thrombosis in devices (n = 18, ROR = 264.71), shock (n = 119, ROR = 186.27) and anaphylactoid shock (n = 4, ROR = 143.45). In contrast, sodium citrate-related AEs primarily included systemic diseases with various reactions at the administration site (15.75%) and gastrointestinal disorders (11.63%). The reporting proportion of mortality for sodium citrate (2.83%) was higher than that for NM, although this finding may be influenced by reporting bias and confounding by indication. In addition, this study detected signals not described in the instructions, such as citrate toxicity (ROR = 6,740.61) and spinal muscular atrophy (ROR = 665.94). Both drugs shared several high-incidence AEs, including pruritus, vomiting and dyspnea, but there are significant differences in gender, age and geographical distribution.ConclusionThe use of NM was associated with a strong disproportionality signal for severe immune-related AEs, such as anaphylactic shock, and requires strengthened monitoring. The metabolic complications of sodium citrate and its exposure risks during pregnancy require targeted optimization of medication strategies. Real-world data suggested that both drugs may cause AEs that were not mentioned in the instructions, so risk management needs to be improved through dynamic pharmacological vigilance. This study provided important references for individualized selection and safety management of anticoagulation regimens for patients requiring hemodialysis.

Depression is a psychological condition in adolescents caused by various factors. Many serious consequences can be associated with depression, such as irritability, emotional instability, and suicide. Meanwhile, the incidence of depression and suicide among adolescents was also affected during the pandemic of COVID-19 in 2019. This phenomenon of adolescent depression should be drawn extensive concern by the community, which affects their physical and mental health. This review describes the epidemiology, high-risk factors, and treatment of adolescent depression. The onset of depression is probably attributable to preterm birth, growth environment, genetic. We also identify that the COVID-19 pandemic, initiated in late 2019,affects adolescent mental health. Antidepressants and psychotherapy are conventional treatments for depressive disorders. However, it is controversial whether antidepressants are as effective and safer as psychotherapy, and a combination of the two could provide more benefit to this population than antidepressants alone. We also summarize some antidepressants developed for novel targets. Improving the efficacy and safety of treatment to reduce the suicide rate among adolescents is the primary goal of clinical research. Existing treatment modalities and drugs are not sufficient to achieve clinical demands, so that new therapeutic targets will be promising for such patients. A variety of factors can contribute to depression in adolescents. Adolescent depression should be mainly treated with non-pharmacological. A combination of guideline-recommended antidepressants should be used if uncontrolled with non-pharmacological, but adverse drug reactions and suicidal ideation should be closely monitored.

Congenital valve defects account for a substantial proportion of cardiovascular malformations, yet the molecular mechanisms orchestrating cardiac valve development remain incompletely elucidated. While Bone morphogenetic protein (BMP) signaling is essential for valvulogenesis, the specific contributions of individual BMP ligands, particularly the teleost-specific bmp16, have not been characterized. Using the CRISPR/Cas9 system, we generated a bmp16 null knockout and delineated critical roles of this ligand in valvular morphogenesis. bmp16 knockout embryos display a significant reduction in Sox9-positive valvular cells and exhibit severely dysplastic arterial valves, characterized by increased interleaflet distance, thickened leaflets, and shortened leaflet lengths. These morphological abnormalities correlate with impaired valve function, culminating in progressive blood regurgitation, ventricular dilation, and pericardial edema. Mechanistically, loss of bmp16 or pharmacological inhibition of BMP signaling significantly downregulates notch1b expression in developing valves, while pharmacological activation of Notch signaling rescues the regurgitation phenotype in bmp16 mutants. Collectively, our findings establish bmp16 as a novel regulator of valve development and uncover a functional BMP-Notch signaling axis required for vertebrate valvulogenesis, providing new insights into the molecular mechanisms that govern cardiac valve formation and pathogenesis.

In animals, evolutionarily conserved Polycomb repressive complex 2 (PRC2) catalyzes histone H3 lysine 27 trimethylation (H3K27me3) and PRC1 functions in recruitment and transcriptional repression. However, the mechanisms underlying H3K27me3-mediated stable transcriptional silencing are largely unknown, as PRC1 subunits are poorly characterized in fungi. Here, we report that in the filamentous fungus Magnaporthe oryzae , the N-terminal chromodomain and C-terminal MRG domain of Eaf3 play key roles in facultative heterochromatin formation and transcriptional silencing. Eaf3 physically interacts with Ash1, Eed, and Sin3, encoding an H3K36 methyltransferase, the core subunit of PRC2, and a histone deacetylation co-suppressor, respectively. Eaf3 co-localizes with a set of repressive Ash1-H3K36me2 and H3K27me3 loci and mediates their transcriptional silencing. Furthermore, Eaf3 acts as a histone reader for the repressive H3K36me2 and H3K27me3 marks. Eaf3-occupied regions are associated with increased nucleosome occupancy, contributing to transcriptional silencing in M. oryzae . Together, these findings reveal that Eaf3 is a repressive H3K36me2 reader and plays a vital role in Polycomb gene silencing and the formation of facultative heterochromatin in fungi. The authors characterize a repressive H3K36me2 reader that plays a PRC1-like role in Polycomb gene silencing and facultative heterochromatin formation in fungi that functions through direct interaction with a PRC2 subunit, a histone deacetylation co-suppressor, and nucleosome compaction.

The cast thin sections of tight oil reservoirs contain important parameters such as rock mineral composition and content, porosity, permeability and stratigraphic characteristics, which are of great significance for reservoir evaluation. The use of deep learning technology for intelligent identification of thin section images is a development trend of mineral identification. However, the difficulty of making cast thin sections, the complexity of the making process and the high cost of thin section annotation have led to a lack of cast thin section images, which cannot meet the training requirements of deep learning image recognition models. In order to increase the sample size and improve the training effect of deep learning model, we proposed a generation and annotation method of thin section images of tight oil reservoir based on deep learning, by taking Fuyu reservoir in Sanzhao Sag as the target area. Firstly, the Augmentor strategy space was used to preliminarily augment the original images while preserving the original image features to meet the requirements of the model. Secondly, the category attention mechanism was added to the original StyleGAN network to avoid the influence of the uneven number of components in thin sections on the quality of the generated images. Then, the SALM annotation module was designed to achieve semi-automatic annotation of the generated images. Finally, experiments on image sharpness, distortion, standard accuracy and annotation efficiency were designed to verify the advantages of the method in image quality and annotation efficiency.

Although recent studies have highlighted the link of TIPE2 and asthma airway inflammation, its roles and molecular mechanisms in different asthma inflammatory phenotypes remain largely unknown. We evaluated sputum TIPE2 expression level and its correlation with different asthma phenotypes. Additionally, we explored the roles and mechanism of TIPE2 in M1 polarization of macrophages. A total of 102 asthma patients who underwent sputum induction were enrolled to evaluate the expression level of TIPE2 and its association with different asthma phenotypes. To explore the roles and mechanism of TIPE2 in M1 polarization of macrophages, THP-1 monocytes stimulated with phorbol-12-myristate-13-acetate, were used as a model of undifferentiated (M0) macrophages, and M0 macrophages were treated with lipopolysaccharide to induce M1 macrophages. The sputum TIPE2 level was significantly lower in patients with neutrophilic asthma (NA) and higher in patients with eosinophilic asthma (EA) compared with patients with paucigranulocytic asthma. The levels of IL-1β, TNF-α and IL-6 were highest in NA compared with other groups. TIPE2 levels in sputum negatively correlated with IL-1β and TNF-α levels but positively correlated with IL-4, IL-5, IL-13, and IL-10 levels ( < 0.05). , TIPE2 enhanced Nrf2/HO-1 pathway activation in macrophages and inhibited LPS-induced M1 macrophage differentiation and related cytokine release. Further analysis showed that the Nrf2 inhibitor ML385 weakened TIPE2-induced activation of the Nrf2/HO-1 pathway, as well as TIPE2-induced suppression in M1 polarization of macrophage and inflammatory cytokines secretion. TIPE2 expression level was highly down-regulated in NA and was negatively correlated with inflammatory factors (IL-1β and TNF-α). Aberrant expression of TIPE2 may target the Nrf2/HO-1 pathway to inhibit M1 macrophage-related neutrophilic inflammation in asthma.

Background Patterns of regional failure after intensity-modulated radiotherapy (IMRT) provide crucial evidence for optimizing target delineation in nasopharyngeal carcinoma (NPC). However, the specific patterns of regional recurrence after IMRT for NPC remain to be fully elucidated to optimize elective neck irradiation (ENI). Methods A total of 145 patients with NPC who developed regional recurrence after definitive IMRT between 2012 and 2022 were retrospectively reviewed. Recurrent lymph nodes were mapped onto the original pretreatment imaging, and each failure was categorized as either within or outside the initially involved field. Overall survival (OS) was estimated using the Kaplan-Meier method. Results Regional recurrence most frequently occurred in level IIb (55.1%), followed by level IIa (40.7%), level III (26.9%), level IV (17.2%), levels Va (11.7%) and Vb (11.0%), with infrequent involvement of the retropharyngeal (10.3%) and parotid (6.9%) regions. Most failures (95.2%) occurred within initially involved areas, while out-involved field recurrences were rare (4.8%), predominantly in the lower neck, and no skip metastasis was observed, suggesting a pattern of contiguous spread rather than de novo failure. The 5-year overall survival rate was 69.4%, and 74.2% among patients who underwent salvage surgery. Conclusions Regional recurrence after IMRT for NPC was mainly confined to initially involved areas, with out-involved-field recurrences being rare. These findings, combined with favorable outcomes following salvage treatment, serve as a valuable reference for optimizing ENI strategies. Clinical trial number Not applicable.