Ethionine-induced S-adenosylmethionine deficiency suppressed H3K27me3 and cell differentiation during neural tube development in mice.

S-adenosylmethionine (SAM) as a major methyl donor plays a key role in methylation modification in vivo, and its disorder was closely related to neural tube defects (NTDs). However, the exact mechanism between SAM deficiency and NTDs remained unclearly. Hence, we investigated the association between histone methylation modification and cell differentiation in NTDs mice induced by SAM deficiency. The levels of SAM and SAH (S-adenosylhomocysteine) were determined by enzyme linked immunosorbent assay (ELISA). The level of histone methylation, ß-catenin were analyzed by Western blot, reversing transcription and quantitative PCR (RT-qPCR) and immunofluorescence. The results showed that the incidence rate of NTDs induced by ethionine were 46.2%. Post treatment of ethionine combined with SAM, the incidence rate of NTDs was reduced to 26.2%. The level of SAM was significantly decreased (p < 0.05) and a reduction in the SAM/SAH ratio was observed after entionine treatment. The SAM deficiency caused the reduction of H3K27me3 modifications and the elevated UTX activity (p < 0.05), and inhibited the expressions of ß-catenin. The differentiations of NSCs into neurons and oligodendrocytes were inhibited under SAM deficiency (p < 0.05). These results indicated that the SAM deficiency led to reduce H3K27me3 modifications, prevented the ß-catenin signaling pathway and NSCs differentiation, which provided an understanding of the novel function of epigenetic regulation in NTDs.

Unlocking the solution-phase molecular transformation of biochar during intensive rainfall events: Implications for the long-term carbon cycle under climate change.

The unclear turnover of soluble and solid phases of biochar during increasingly severe climate change (e.g., intensive rainfall) raised questions about the carbon stability of biochar in soil. Here, we present an in-depth analysis of the molecular-level transformations occurring in both the soluble and solid phases of biochar subjected to prolonged wet-dry cycles with simulated rainwater. Biochar properties, including surface functionality and carbon texture, greatly affected the transformation route and led to a distinct stability variation. The rich alkyl -CH3 on the low-temperature biochar (450 °C) was oxidized to hydroxymethyl -CH2OH or formyl -CHO, and the ester -COOC- or peptide -CONHC- bonds were fragmented in the meantime, causing the release of protein- or lipid-like organic carbon and the declined carbon stability (Æ, tested by H2O2 oxidation, from 60.1% to 53.2%). After a high-temperature (750 °C) pyrolysis process, only oxidation of the surface -OH with limited bond breaking occurred after rainwater elution, presenting a marginal composition difference with constant stability. However, the fragile carbon nature of biochar, caused by CO2 activation, led to enhanced fragmentation, oxidation, and hydration, resulting in the release of tannin-like organic carbon, which compromised the carbon storage (Æ decreased from 81.2% to 73.0%). Our findings evaluated the critical transformation of biochar during intensive rainfall, offering crucial insights for designing sustainable biochar and achieving carbon neutrality.

EMC3 regulates trafficking and pulmonary toxicity of the SFTPCI73T mutation associated with interstitial lung disease.

The most common mutation in surfactant protein C gene (SFTPC), SFTPCI73T, causes interstitial lung disease with few therapeutic options. We previously demonstrated that EMC3, an important component of the multiprotein endoplasmic reticulum membrane complex (EMC), is required for surfactant homeostasis in alveolar type 2 epithelial (AT2) cells at birth. In the present study, we investigated the role of EMC3 in the control of SFTPCI73T metabolism and its associated alveolar dysfunction. Using a knock-in mouse model phenocopying the I73T mutation, we demonstrated that conditional deletion of Emc3 in AT2 cells rescued alveolar remodeling/simplification defects in neonatal and adult mice. Proteomic analysis revealed that Emc3 depletion reversed the disruption of vesicle trafficking pathways and rescued the mitochondrial dysfunction associated with I73T mutation. Affinity purification-mass spectrometry analysis identified potential EMC3 interacting proteins in lung AT2 cells, including Valosin Containing Protein (VCP) and its interactors. Treatment of SftpcI73T knock-in mice and SFTPCI73T expressing iAT2 cells derived from SFTPCI73T patient-specific iPSCs with the specific VCP inhibitor CB5083 restored alveolar structure and SFTPCI73T trafficking respectively. Taken together, the present work identifies the EMC complex and VCP in the metabolism of the disease-associated SFTPCI73T mutant, providing novel therapeutical targets for SFTPCI73T-associated interstitial lung disease.

Size effect of ZIF-8 based nanocarrier pesticide delivery system on targeted release and insecticidal activity.

BACKGROUND: Traditional chemical pesticides are easily lost by surface runoff and only small quantities reach the target, thus causing serious environmental pollution. In this work, dinotefuran@zeolitic imidazolate framework-8@polydopamine@zein (DNF@ZIF-8@PDA@zein), was constructed to deliver DNF with pH and enzyme double response of release, thereby achieving targeted release and efficient long-term pest control. RESULTS: DNF@ZIF-8@PDA@zein was synthesized with three hydrated diameters (249.73 ± 9.99 nm, 142.94 ± 5.63 nm and 75.16 ± 4.66 nm, respectively). The release of DNF from DNF@ZIF-8@PDA@zein after 28 h was significantly higher at pH 5.0 (89.22 ± 7.18%) compared to that at pH 8 (81.8 ± 6.11%). Protease-assisted release of DNF was notably higher than that without protease (pH 5: 89.22 ± 5.55% versus 27.19 ± 3.22%; pH 8: 81.8 ± 6.11% versus 25.39 ± 3.87%). The stimuli-responsive release of DNF from DNF@ZIF-8@PDA@zein increased with decreased particle size due to increased pore size, reduced binding forces (i.e., weaker π-π stacking, hydrogen bonding, and Zn-N covalent bonding), and the shortening of diffusion path, leading to faster disintegration and drug release. Additionally, the anti-photolysis ability of DNF@ZIF-8@PDA@zein was 3.2 times that of pure DNF. The insecticidal activity improved with smaller nanoparticles due to higher drug release rate and greater inhibition of detoxification enzyme activity by more zinc ion (Zn2+) dissolution. CONCLUSION: The pH and enzyme dual-responsive release as well as insecticidal activity of DNF@ZIF-8@PDA@zein increase with decreased nanoparticle size, showing effective pest management in long-term and potential application prospects in sustainable agriculture. © 2024 Society of Chemical Industry.

Temporal succession of micropropagules during accumulation and dissipation of green tide algae: A case study in Rudong coast, Jiangsu Province.

Over the past 18 years, green tides have persistently occurred in the Yellow Sea. Micropropagules of these algae are key to bloom formation, yet their species composition and succession during dissipation remain underexplored. During the dissipation process of accumulated green tide algae, a large number of micropropagules are released. This study monitored the dissipation of green tide algae at a coastal site, tracking micropropagules in water and sediment using an internal transcribed spacer (ITS) and 5S rDNA primers. Results showed that the dissipation lasted about one month, with significant micropropagule release. Initially, micropropagules matched 5S-II Ulva prolifera, but later species like Ulva torta, Ulva simplex, Ulva flexuosa, and Ulva meridionalis emerged. Ulva meridionalis dominated sediment in July and August, while U. torta was prevalent in water, and U. flexuosa was dominant in other months. Accumulated U. prolifera in the intertidal zone may not contribute to the seeding of the next year's bloom. This study sheds light on the dissipation process and succession patterns of micropropagules in coastal environments.

Novel Dual PPAR δ/γ Partial Agonist Induces Hepatic Lipid Accumulation through Direct Binding and Inhibition of AKT1 Phosphorylation, Mediating CD36 Upregulation.

ZLY06 is a dual agonist of peroxisome proliferator-activated receptor (PPAR) δ/γ, showing potential therapeutic effects on metabolic syndrome. However, our research has revealed that ZLY06 exhibits hepatotoxicity in normal C57BL/6J mice, though the precise mechanism remains unclear. This study aims to investigate the manifestations and mechanisms of ZLY06-induced hepatotoxicity. We administered ZLY06 via oral gavage to C57BL/6J mice (once daily for six weeks) and monitored various indicators to preliminarily explore its hepatotoxicity. Additionally, we further investigate the specific mechanisms of ZLY06-induced hepatotoxicity using PPAR inhibitors (GW9662 and GSK0660) and the Protein kinase B (AKT) activator (SC79). Results showed that ZLY06 led to increased serum ALP, ALT and AST, as well as elevated liver index and hepatic lipid levels. There was upregulation in the gene and protein expression of lipid metabolism-related molecules Acc, Scd1, Cd36, Fabp1 and Fabp2 in hepatocytes, with Cd36 showing the most significant change. Furthermore, cotreatment with SC79 significantly reduced ZLY06-induced hepatotoxicity in AML12 cells, evidenced by decreased intracellular TG levels and downregulation of CD36 expression. Specific knockdown of CD36 also mitigated ZLY06-induced hepatotoxicity. The study found that ZLY06 may bind to AKT1, inhibiting its phosphorylation activation, with the downregulation of p-AKT1 preceding the upregulation of CD36. In summary, ZLY06 mediates the upregulation of CD36 by potentially binding to and inhibiting the phosphorylation of AKT1, leading to hepatic lipid metabolism disorder and inducing liver toxicity.

Causal relationship between 731 immune cells and the risk of diabetic nephropathy: a two­sample bidirectional Mendelian randomization study.

OBJECTIVE: Previous observational studies have indicated associations between various immune cells and diabetic nephropathy (DN). However, the causality remains unclear. We aimed to further evaluate the causal association between immune cells and DN using bidirectional two-sample Mendelian randomization (MR) analysis. METHOD: The DN data were retrieved from the IEU OpenGWAS Project database, while the data for 731 immune cells were sourced from GWAS summary statistics by Orru ̀ et al. The investigation into the causal relationship between immune cells and DN employed the inverse variance weighted (IVW), weighted median (WME), and MR-Egger methods. The stability and reliability of the findings underwent evaluation through Cochran's Q test, MR-Egger intercept's P-value, MR-PRESSO, and Leave-One-Out (LOO) method. RESULT: The IVW estimates suggested a positive causal effect of CD25 on IgD-CD38dim B cell, CD25 on naive-mature B cell, CD127 on granulocyte, SSC-A on HLA DR + Natural Killer, HLA DR on plasmacytoid Dendritic Cell, and HLA DR on Dendritic Cell on DN. Conversely, the abundance of Myeloid Dendritic Cell, CD62L- Dendritic Cell %Dendritic Cell, CD86+ myeloid Dendritic Cell %Dendritic Cell, CD14- CD16-, CX3CR1 on CD14- CD16-, and SSC-A on CD4+ T cell had negative causal effects on DN. However, after correcting the P value for significant causality results using the FDR method, it was concluded that only Myeloid Dendritic Cells had a causal relationship with DN (FDR-p = 0.041), while the other immune cells showed no significant association with DN, so their relationship was suggestive. The results were stable with no observed horizontal pleiotropy and heterogeneity. Reverse MR analysis indicated no causal relationship between DN and the increased risk of positively identified immune cells. CONCLUSION: This study provides an initial insight into the genetic perspective of the causal relationship between immune cells and DN. It establishes a crucial theoretical foundation for future endeavors in precision medicine and individualized treatment.

Comparative Evaluation Between Cutting of the Intersphincteric Space vs Cutting Seton in High Anal Fistula: A Randomized Controlled Trial.

BACKGROUND: This study compared the efficacy of cutting of the intersphincteric space (COIS) with cutting seton (CS) procedure in treating high anal fistula. METHODS: Patients diagnosed with high anal fistula were allocated into groups, who randomly received COIS and CS procedures. The primary outcome was wound healing time. Secondary outcomes included surgical parameters (operation time, hospital stay, and hospitalization expense), anal sphincter function, wound pain, wound size, clinical efficacy, recurrence after 12 months of follow-up, and complications. RESULTS: A total of 72 patients participated (36 in each group). The wound healing time was notably shorter in the COIS group than the CS group (35.75 ± 11.15 vs. 55.69 ± 13. 42 days; P< 0.001). The COIS group also demonstrated superior basic surgical parameters compared to the CS group (P< 0.001). Postoperatively, the COIS group exhibited significantly higher anal resting pressure and anal maximum contractile pressure than the CS group at 3 months postoperatively (58.39 ± 6.72 vs. 51.25 ± 4.33 mmHg; P< 0.001 and 143.72 ± 8.25 vs. 126.75 ± 11.49 mmHg; P< 0.001). The Wexner incontinence score at 3 months post-operation in the COIS group was significantly lower than in the CS group (0.50;0.00,1.00 vs. 3.00; 3.00,4.00; P< 0.001). The recurrence rate was 2.78% in the COIS group and 8.33% in the CS group without statistically difference (P= 0.607). CONCLUSION: In comparison to the CS procedure, COIS appears to be an effective treatment option for high anal fistulas, offering quicker wound healing time, enhanced sphincter function, less pain, minimal invasiveness, and cost-efficiency, while maintaining a high healing rate and low recurrence rate.

The use of adjuvant chemotherapy combined with concurrent chemoradiotherapy enhances survival rates in cases of locally advanced nasopharyngeal carcinoma.

This study aimed to evaluate the impact of adjuvant chemotherapy on survival rates, adverse events, and quality of life (QOL) in patients with locally advanced nasopharyngeal carcinoma (NPC). A retrospective cohort study was conducted, including patients with firstly histologically confirmed non-metastatic stage III-IVB NPC between February 2018 and February 2020, and with continuous follow-up data available, were chosen from the medical records of the affiliated hospital of Qingdao University and Zibo Central Hospital. There were 395 patients receiving concurrent chemoradiotherapy (CCRT) with adjuvant chemotherapy (adjuvant chemotherapy group) and 428 patients receiving CCRT alone (control group). The two groups were compared for treatment response, adverse events, and QOL scores. Besides, Kaplan-Meier plots, and multivariate COX analysis were conducted. The adjuvant chemotherapy group demonstrated a significantly higher overall survival and disease-free survival compared to the control group. The use of adjuvant chemotherapy was significantly correlated with improved overall survival and disease-free survival. Adjuvant chemotherapy was associated with reduced local recurrence and distant metastasis rates. However, higher rates of adverse events were observed in the adjuvant chemotherapy group. QOL scores for physical functioning, emotional functioning, and overall quality of life were higher in the adjuvant chemotherapy group. The findings of this study indicate that adjuvant chemotherapy in locally advanced NPC is associated with improved treatment response, extended overall and disease-free survivals, and better QOL, despite higher rates of adverse events.

Changes in Intramedullary Increased Signal Intensity on Axial T2-weighted MRI After Laminoplasty for Cervical Spondylotic Myelopathy: A 10-year Follow-up Study.

STUDY DESIGN: A retrospective study. OBJECTIVE: To investigate whether the preoperative classification and changes in the intramedullary increased signal intensity (ISI) on axial T2-weighted magnetic resonance imaging (MRI) reflect the postoperative functional outcome in patients after laminoplasty for cervical spondylotic myelopathy (CSM). SUMMARY OF BACKGROUND DATA: Although patients with CSM exhibit ISI on axial MRI, the association between ISI (preoperative classification and changes) and surgical outcomes has not been investigated. PATIENTS AND METHODS: We retrospectively included patients with CSM who underwent MRI preoperatively and at least 10 years postoperatively after laminoplasty between January 2009 and December 2010. According to axial images for the cervical compressive myelopathy (Ax-CCM) system, the ISI on axial images was classified as follows: type 0, normal; type 1, diffuse; type 2, fuzzy focal; and type 3, discrete focal. Functional outcomes, as measured by the Japanese Orthopaedic Association (JOA) score and JOA recovery rate, were evaluated based on the Ax-CCM classification. RESULTS: Forty-three patients were enrolled. The mean follow-up time was 11.0±1.0 years. At the final follow-up, postoperative changes in the type of ISI were observed in 62.8% of patients. The type of ISI improved in 5 patients (11.6%), remained unchanged in 16 patients (37.2%), and worsened in 22 patients (51.2%). Patients with preoperative type 2 ISI had worse postoperative JOA scores and JOA recovery rates than those with other types. A worse ISI type was related to a lower postoperative JOA score and a lower recovery rate at the final follow-up. CONCLUSIONS: Type 2 ISI was associated with poor postoperative symptoms and low postoperative function improvement. ISI changed after laminoplasty in 27 patients (62.8%), and worsened ISI was related to poor surgical outcomes.

Programmable Lanthanide Metal-Organic Framework for Ultra-Efficient Nucleic Acids Extraction and Interaction Analysis.

Efficient, mild, and reversible adsorption of nucleic acids onto nanomaterials represents a promising analytical approach for medical diagnosis. However, there is a scarcity of efficient and reversible nucleic acid adsorption nanomaterials. Additionally, the lack of comprehension of the molecular mechanisms governing their interactions poses significant challenges. These issues hinder the rational design and analytical applications of the nanomaterials. Herein, we propose an ultra-efficient nucleic acid affinity nanomaterial based on programmable lanthanide metal-organic frameworks (Ln-MOFs). Through experiments and density functional theory calculations, a rational design guideline for nucleic acid affinity of Ln-MOF was proposed, and a modular and flexible preparation scheme was provided. Then, Er-TPA (terephthalic acid) MOF emerged as the optimal candidate due to its pore size-independent adsorption and desorption capabilities for nucleic acids, enabling ultra-efficient adsorption (about 150% mass ratio) within 1 min. Furthermore, we elucidate the molecular-level mechanisms underlying the Ln-MOF adsorption of single- and double-stranded DNA and G4 structures. The affinity nanomaterial based on Ln-MOF exhibits robust nucleic acid extraction capability (4-fold higher than commercial reagent kits) and enables mild and reversible CRISPR/Cas9 functional regulation. This method holds significant promise for broad application in DNA/RNA liquid biopsy and gene editing, facilitating breakthroughs in analytical chemistry, pharmacy, and medical research.

Frontoparietal Response to Working Memory Load Mediates the Association between Sleep Duration and Cognitive Function in Children.

Lack of sleep has been found to be associated with cognitive impairment in children, yet the neural mechanism underlying this relationship remains poorly understood. To address this issue, this study utilized the data from the Adolescent Brain Cognitive Development (ABCD) study (n = 4930, aged 9-10), involving their sleep assessments, cognitive measures, and functional magnetic resonance imaging (fMRI) during an emotional n-back task. Using partial correlations analysis, we found that the out-of-scanner cognitive performance was positively correlated with sleep duration. Additionally, the activation of regions of interest (ROIs) in frontal and parietal cortices for the 2-back versus 0-back contrast was positively correlated with both sleep duration and cognitive performance. Mediation analysis revealed that this activation significantly mediated the relationship between sleep duration and cognitive function at both individual ROI level and network level. After performing analyses separately for different sexes, it was revealed that the mediation effect of the task-related activation was present in girls (n = 2546). These findings suggest that short sleep duration may lead to deficit in cognitive function of children, particularly in girls, through the modulation of frontoparietal activation during working memory load.

Integrated analysis of microbiome and host transcriptome unveils correlations between lung microbiota and host immunity in bronchoalveolar lavage fluid of pneumocystis pneumonia patients.

OBJECTIVE: The lung microbiota of patients with pulmonary diseases is disrupted and impacts the immunity. The microbiological and immune landscape of the lungs in patients with pneumocystis pneumonia (PCP) remains poorly understood. METHODS: Multi-omics analysis and machine learning were performed on bronchoalveolar lavage fluid to explore interaction between the lung microbiota and host immunity in PCP. Then we constructed a diagnostic model using differential genes with LASSO regression and validated by qPCR. The immune infiltration analysis was performed to explore the landscape of lung immunity in patients with PCP. RESULTS: Patients with PCP showed a low alpha diversity of lung microbiota, accompanied by the elevated abundance of Firmicutes, and the differential expressed genes (DEGs) analysis displayed a downregulation of MAPK signaling. The MAPK10, TGFB1, and EFNA3 indicated a potential to predict PCP (AUC = 0.86). The lung immune landscape in PCP showed the lower levels of naïve CD4+ T cells and activated dendritic cells. The correlation analysis of the MAPK signaling pathway-related DEGs and the differential microorganisms at the level of phylum showed that the Firmicutes was negatively correlated with these DEGs. CONCLUSION: We profiled the characteristics of lung microbiota and immune landscape in PCP, which may contribute to elucidating the mechanism of PCP.

The gut microbiota-aromatic hydrocarbon receptor (AhR) axis mediates the anticolitic effect of polyphenol-rich extracts from Sanghuangporus.

Inflammatory bowel disease (IBD) is a significant global health concern. The gut microbiota plays an essential role in the onset and development of IBD. Sanghuangporus (SH), a traditional Chinese medicinal mushroom, has excellent anti-inflammatory effects and is effective at modulating the gut microbiota. Despite these attributes, the specific anticolitic effects of SH and the mechanisms through which the gut microbiota mediates its benefits remain unclear. Herein, we demonstrated that polyphenol-rich extract from SH effectively alleviated the pathological symptoms of dextran sodium sulfate (DSS)-induced colitis in mice by modulating the gut microbiota. Treatment with SH distinctly enriched Alistipes, especially Alistipes onderdonkii, and its metabolite 5-hydroxyindole-3-acetic acid (5HIAA). Oral gavage of live A. onderdonkii or 5HIAA potently mitigated DSS-induced colitis in mice. Moreover, both 5HIAA and SH significantly activated the aromatic hydrocarbon receptor (AhR), and the administration of an AhR antagonist abrogated their protective effects against colitis. These results underscore the potent efficacy of SH in diminishing DSS-induced colitis through the promotion of A. onderdonkii and 5HIAA, ultimately activating AhR signaling. This study unveils potential avenues for developing therapeutic strategies for colitis based on the interplay between SH and the gut microbiota.

Diosgenin attenuates metabolic-associated fatty liver disease through the hepatic NLRP3 inflammasome-dependent signaling pathway.

Metabolic-associated fatty liver disease (MAFLD) is one of the most common liver diseases worldwide; however, its pathogenesis and treatment methods have not been perfected. NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) is a promising therapeutic target for MAFLD. Diosgenin (DG) is a natural compound that was identified in a traditional Chinese herbal medicine, which has pharmacological effects, such as anti-inflammatory, antioxidant, hepatoprotective, and hypolipidemic activities. In this study, we examined the effects and molecular mechanisms of DG on MAFLD in vitro and in vivo. We established a rat model by administering a high-fat diet (HFD). We also generated an in vitro MAFLD model by treating HepG2 cells with free fatty acids (FFAs). The results indicated that DG attenuated lipid accumulation and liver injury in both in vitro and in vivo models. DG downregulated the expression of NLRP3, apoptosis-associated speckle-like protein (ASC), cysteinyl aspartate specific proteinase-1 (caspase-1), gasdermin D (GSDMD), GSDMD-n, and interleukin-1ß (IL-1ß). In addition, we silenced and overexpressed NLRP3 in vitro to determine the effects of DG on antiMAFLD. Silencing NLRP3 enhanced the effect of DG on the treatment of MAFLD, whereas NLRP3 overexpression reversed its beneficial effects. Taken together, the results show that DG has a favorable effect on attenuating MAFLD through the hepatic NLRP3 inflammasome-dependent signaling pathway. DG represents a natural NLRP3 inhibitor for the MAFLD treatment.

Identification of disulfidptosis-associated genes and characterization of immune cell infiltration in thyroid carcinoma.

OBJECTIVE: The primary objective of this study is to conduct a comprehensive screening and analysis of differentially expressed genes related to disulfidoptosis (DEDRGs) in thyroid carcinoma (THCA). This entails delving into the intricate characterization of immune cell infiltration within the THCA context and subsequently formulating and validating a novel prognostic model. METHOD: To achieve our objectives, we first delineated two distinct subtypes of disulfidoptosis-related genes (DRGs) via consensus clustering methodology. Subsequently, employing the limma R package, we identified the DEDRGs critical for our investigation. These DEDRGs underwent meticulous validation across various databases, alongside an in-depth analysis of gene regulation. Employing functional enrichment techniques, we explored the potential molecular mechanisms underlying disulfidoptosis in THCA. Furthermore, we scrutinized the immune landscape within the two identified subtypes utilizing CIBERSORT and ESTIMATE algorithms. The construction of the prognostic model for THCA entailed intricate methodologies including univariate, multivariate Cox regression, and LASSO regression algorithms. The validity and efficacy of our prognostic model were corroborated through Kaplan-Meier survival curves and ROC curves. Additionally, a nomogram was meticulously formulated to facilitate the prediction of patient prognosis. To fortify our findings, we conducted a comprehensive Bayesian co-localization analysis coupled with rigorous in vitro experimentation, aimed at unequivocally establishing the validity of the identified DEDRGs. RESULT: Our analyses unveiled Cluster C1, characterized by elevated expression levels of DEDRGs, as harboring a favorable prognosis accompanied by abundant immune cell infiltration. Correlation analyses underscored predominantly positive associations among the DEDRGs, further affirming their significance in THCA. Differential expression patterns of DEDRGs between tumor samples and normal tissues were evident across the GEPIA and HPA databases. Insights from the TIMER database underscored a robust correlation between DEDRGs and immune cell infiltration. KEGG analysis elucidated the enrichment of DEDRGs primarily in pivotal pathways including MAPK, PPAR signaling pathway, and Proteoglycans in cancer. Furthermore, analyses using CIBERSORT and ESTIMATE algorithms shed light on the crucial role played by DEDRGs in shaping the immune microenvironment. The prognostic model, anchored by five genes intricately associated with THCA prognosis, exhibited commendable predictive accuracy and was intricately linked to the tumor immune microenvironment. Notably, patients categorized with low-risk scores stood to potentially benefit more from immunotherapy. The validation of DEDRGs unequivocally underscores the protective role of INF2 in THCA. CONCLUSION: In summary, our study delineates two discernible subtypes intricately associated with DRGs, revealing profound disparities in immune infiltration and survival prognosis within the THCA milieu. The implications of our findings extend to potential treatment strategies for THCA patients, which could entail targeted interventions directed towards DEDRGs and prognostic genes, thereby influencing disulfidptosis and the immune microenvironment. Moreover, the robust predictive capability demonstrated by our prognostic model, based on the five genes (ANGPTL7, FIRRE, ODAPH, PROKR1, SFRP5), underscores its potential clinical utility in guiding personalized therapeutic approaches for THCA patients.

Diosgenin attenuates nonalcoholic hepatic steatosis through the hepatic SIRT1/PGC-1α pathway.

The prevalence of nonalcoholic fatty liver disease (NAFLD) has been increasing worldwide in recent years, causing severe economic and social burdens. Therefore, the lack of currently approved drugs for anti-NAFLD has gradually gained attention. SIRT1, as a member of the sirtuins family, is now the most widely studied in the pathophysiology of many metabolic diseases, and has great potential for preventing and treating NAFLD. Natural products such as Diosgenin (DG) have the potential to be developed as clinical drugs for the treatment of NAFLD due to their excellent multi-target therapeutic effects. In this study, we found that DG can activate the SIRT1/PGC-1α pathway and upregulate the expression of its downstream targets nuclear respiratory factor 1 (NRF1), complex IV (COX IV), mitofusin-2 (MFN2), and PPARα (perox-isome proliferator-activated receptor α) in SD rats induced by high-fat diet (HFD) and HepG2 cells caused by free fatty acids (FFAs, sodium oleate: sodium palmitate = 2:1). Conversely, the levels of dynamin-related protein 1 (DRP1) and inflammatory factors, including NF-κB p65, IL6, and TNFα, were downregulated both in vitro and in vivo. This improved mitochondrial dysfunction, fatty acid oxidation (FAO), lipid accumulation, steatosis, oxidative stress, and hepatocyte inflammation. Subsequently, we applied SIRT1 inhibitor EX527 and SIRT1 agonist SRT1720 to confirm further the necessity of activating SIRT1 for DG to exert therapeutic effects on NAFLD. In summary, these results further demonstrate the potential therapeutic role of DG as a SIRT1 natural agonist for NAFLD. (Graphical Abstracts).

Development of spontaneous recurrent seizures accompanied with increased rates of interictal spikes and decreased hippocampal delta and theta activities following extended kindling in mice.

Interictal epileptiform discharges refer to aberrant brain electrographic signals between seizures and feature intermittent interictal spikes (ISs), sharp waves, and/or abnormal rhythms. Recognition of these epileptiform activities by electroencephalographic (EEG) examinations greatly aids epilepsy diagnosis and localization of the seizure onset zone. ISs are a major form of interictal epileptiform discharges recognized in animal models of epilepsy. Progressive changes in IS waveforms, IS rates, and/or associated fast ripple oscillations have been shown to precede the development of spontaneous recurrent seizures (SRS) in various animal models. IS expressions in the kindling model of epilepsy have been demonstrated but IS changes during the course of SRS development in extended kindled animals remain to be detailed. We hence addressed this issue using a mouse model of kindling-induced SRS. Adult C57 black mice received twice daily hippocampal stimulations until SRS occurrence, with 24-h EEG monitoring performed following 50, 80, and ≥ 100 stimulations and after observation of SRS. In the stimulated hippocampus, increases in spontaneous ISs rates, but not in IS waveforms nor IS-associated fast ripples, along with decreased frequencies of hippocampal delta and theta rhythms, were observed before SRS onset. Comparable increases in IS rates were further observed in the unstimulated hippocampus, piriform cortex, and entorhinal cortex, but not in the unstimulated parietal cortex and dorsomedial thalamus. These data provide original evidence suggesting that increases in hippocampal IS rates, together with reductions in hippocampal delta and theta rhythms are closely associated with development of SRS in a rodent kindling model.

Up-regulation of miR-10a-5p expression inhibits the proliferation and differentiation of neural stem cells by targeting Chl1.

Neural tube defects (NTDs) are characterized by the failure of neural tube closure during embryogenesis and are considered the most common and severe central nervous system anomalies during early development. Recent microRNA (miRNA) expression profiling studies have revealed that the dysregulation of several miRNAs plays an important role in retinoic acid (RA)-induced NTDs. However, the molecular functions of these miRNAs in NTDs remain largely unidentified. Here, we show that miR-10a-5p is significantly upregulated in RA-induced NTDs and results in reduced cell growth due to cell cycle arrest and dysregulation of cell differentiation. Moreover, the cell adhesion molecule L1-like ( Chl1) is identified as a direct target of miR-10a-5p in neural stem cells (NSCs) in vitro, and its expression is reduced in RA-induced NTDs. siRNA-mediated knockdown of intracellular Chl1 affects cell proliferation and differentiation similar to those of miR-10a-5p overexpression, which further leads to the inhibition of the expressions of downstream ERK1/2 MAPK signaling pathway proteins. These cellular responses are abrogated by either increased expression of the direct target of miR-10a-5p ( Chl1) or an ERK agonist such as honokiol. Overall, our study demonstrates that miR-10a-5p plays a major role in the process of NSC growth and differentiation by directly targeting Chl1, which in turn induces the downregulation of the ERK1/2 cascade, suggesting that miR-10a-5p and Chl1 are critical for NTD formation in the development of embryos.