FERREG: ferroptosis-based regulation of disease occurrence, progression and therapeutic response.

Ferroptosis is a non-apoptotic, iron-dependent regulatory form of cell death characterized by the accumulation of intracellular reactive oxygen species. In recent years, a large and growing body of literature has investigated ferroptosis. Since ferroptosis is associated with various physiological activities and regulated by a variety of cellular metabolism and mitochondrial activity, ferroptosis has been closely related to the occurrence and development of many diseases, including cancer, aging, neurodegenerative diseases, ischemia-reperfusion injury and other pathological cell death. The regulation of ferroptosis mainly focuses on three pathways: system Xc-/GPX4 axis, lipid peroxidation and iron metabolism. The genes involved in these processes were divided into driver, suppressor and marker. Importantly, small molecules or drugs that mediate the expression of these genes are often good treatments in the clinic. Herein, a newly developed database, named 'FERREG', is documented to (i) providing the data of ferroptosis-related regulation of diseases occurrence, progression and drug response; (ii) explicitly describing the molecular mechanisms underlying each regulation; and (iii) fully referencing the collected data by cross-linking them to available databases. Collectively, FERREG contains 51 targets, 718 regulators, 445 ferroptosis-related drugs and 158 ferroptosis-related disease responses. FERREG can be accessed at https://idrblab.org/ferreg/.

The dysfunction of CD8+ T cells triggered by endometriotic stromal cells promotes the immune survival of endometriosis.

Endometriosis is defined as an oestrogen-dependent and inflammatory gynaecological disease of which the pathogenesis remains unclear. This study aimed to investigate the cellular heterogeneity and reveal the effect of CD8+ T cells on the progress of endometriosis. Three ovarian endometriosis patients were collected, and single-cell RNA sequencing (scRNA-seq) progressed and delineated the cellular landscape of endometriosis containing five cell clusters. The endometrial cells (EMCs) were the major component, of which the mesenchymal cells were preponderant and characterized with increased inflammation and oestrogen synthesis in endometriosis. The proportion of T cells, mainly CD8+ T cells rather than CD4+, was reduced in endometriotic lesions, and the cytokines and cytotoxicity of ectopic T cells were depressed. CD8+ T cells depressed the proliferation of ESCs through inhibiting CDK1/CCNB1 pathway to arrest the cell cycle and triggered inflammation through activating STAT1 pathway. Correspondingly, the coculture with ESCs resulted in the dysfunction of CD8+ T cells through upregulating STAT1/PDCD1 pathway and glycolysis-promoted metabolism reprogramming. The endometriotic lesions were larger in nude mouse models with T-cell deficiency than the normal mouse models. The inhibition of T cells via CD90.2 or CD8A antibody increased the endometriotic lesions in mouse models, and the supplement of T cells to nude mouse models diminished the lesion sizes. In conclusion, this study revealed the global cellular variation of endometriosis among which the cellular count and physiology of EMCs and T cells were significantly changed. The depressed cytotoxicity and aberrant metabolism of CD8+ T cells were induced by ESCs with the activation of STAT1/PDCD1 pathway resulting in immune survival to promote endometriosis.

Multi-omics integration highlights the role of ubiquitination in endometriosis fibrosis.

BACKGROUND: Endometriosis, characterized by the presence of active endometrial-like tissues outside the uterus, causes symptoms like dysmenorrhea and infertility due to the fibrosis of endometrial cells, which involves excessive deposition of extracellular matrix (ECM) proteins. Ubiquitination, an important post-transcriptional modification, regulates various biological processes in human diseases. However, its role in the fibrosis process in endometriosis remains unclear. METHODS: We employed multi-omics approaches on two cohorts of endometriosis patients with 39 samples. GO terms and KEGG pathways enrichment analyses were used to investigate the functional changes involved in endometriosis. Pearson's correlation coefficient analysis was conducted to explore the relationship between global proteome and ubiquitylome in endometriosis. The protein expression levels of ubiquitin-, fibrosis-related proteins, and E3 ubiquitin-protein ligase TRIM33 were validated via Western blot. Transfecting human endometrial stroma cells (hESCs) with TRIM33 small interfering RNA (siRNA) in vitro to explore how TRIM33 affects fibrosis-related proteins. RESULTS: Integration of proteomics and transcriptomics showed genes with concurrent change of both mRNA and protein level which involved in ECM production in ectopic endometria. Ubiquitylomics distinguished 1647 and 1698 ubiquitinated lysine sites in the ectopic (EC) group compared to the normal (NC) and eutopic (EU) groups, respectively. Further multi-omics integration highlighted the essential role of ubiquitination in key fibrosis regulators in endometriosis. Correlation analysis between proteome and ubiquitylome showed correlation coefficients of 0.32 and 0.36 for ubiquitinated fibrosis proteins in EC/NC and EC/EU groups, respectively, indicating positive regulation of fibrosis-related protein expression by ubiquitination in ectopic lesions. We identified ubiquitination in 41 pivotal proteins within the fibrosis-related pathway of endometriosis. Finally, the elevated expression of TGFBR1/α-SMA/FAP/FN1/Collagen1 proteins in EC tissues were validated across independent samples. More importantly, we demonstrated that both the mRNA and protein levels of TRIM33 were reduced in endometriotic tissues. Knockdown of TRIM33 promoted TGFBR1/p-SMAD2/α-SMA/FN1 protein expressions in hESCs but did not significantly affect Collagen1/FAP levels, suggesting its inhibitory effect on fibrosis in vitro. CONCLUSIONS: This study, employing multi-omics approaches, provides novel insights into endometriosis ubiquitination profiles and reveals aberrant expression of the E3 ubiquitin ligase TRIM33 in endometriotic tissues, emphasizing their critical involvement in fibrosis pathogenesis and potential therapeutic targets.

ACEK Biosensor for the Minute-Scale Quantification of Breast Cancer ctDNA.

Circulating tumor DNA (ctDNA) appears as a valuable liquid biopsy biomarker in the early diagnosis, treatment, and prognosis of cancer. Here, a biosensing method derived from the AC electrokinetics (ACEK) effect was constructed in this study for the simple, efficient, and rapid method of detection of ctDNA. In the proof-of-concept experiment, ctDNA from the PIK3CA E542K mutant in breast cancer was quantified by detecting a normalized capacitance change rate using a forked-finger gold electrode as the sensing electrode in combination with the ACEK effect. We compared two formats for the construction of the approach by employing varied immobilization strategies; one is to immobilize the DNA capture probe on the electrode surface by Au-S bonding, while the other immobilizes the probe on a self-assembled membrane on the electrode surface by amide bonding. Both formats demonstrated ultrafast detection speed by completing the ctDNA quantification within 1 min and a linear range of 10 fM-10 pM was observed. Meanwhile, the immobilization via the self-assembled membrane yielded improved stability, sensitivity, and specificity than its Au-S bonding counterpart. A detection limit of 1.94 fM was eventually achieved using the optimized approach. This research provides a label-free and minute-scale universal method for the detection of various malignant tumors. The ctDNA biosensors based on the ACEK effect improved according to the probe type or electrode structure and have potential applications in tumor drug efficacy prediction, drug resistance monitoring, screening of high-risk groups, differential diagnosis, monitoring of tiny residual lesions, and prognosis determination.

Low-Molecular-Weight Peptides Prepared from Hypsizygus marmoreus Exhibit Strong Antioxidant and Antibacterial Activities.

Hypsizygus marmoreus has abundant proteins and is a potential source for the development of bioactive peptides. However, currently, the research on the bioactive components of H. marmoreus mainly focuses on polysaccharides, and there is no relevant research on the preparation of bioactive peptides. In this article, an ultrasound-assisted extraction method was used to extract proteins from H. marmoreus, and then, four peptides with different molecular weight ranges were prepared through protease hydrolysis and molecular classification. The antioxidant and antibacterial activities were also studied. Under the optimal conditions, the extraction rate of H. marmoreus proteins was 53.6%. Trypsin exhibited the highest hydrolysis rate of H. marmoreus proteins. The optimal parameters for enzymatic hydrolysis were a substrate concentration of 3.7%, enzyme addition of 5700 U/g, pH value of 7, extraction temperature of 55 °C, and time of 3.3 h. Under these conditions, the peptide yield was 59.7%. The four types of H. marmoreus peptides were prepared by molecular weight grading. Among them, peptides with low molecular weight (<1 kDa) had stronger antioxidant and antibacterial activities. This study provides a theoretical basis for the efficient preparation of H. marmoreus peptides and the development of antioxidant and antibacterial peptide products.

Calcium signaling facilitates chilling- and GA- induced dormancy release in tree peony.

Calcium plays a crucial role in plant growth and development, yet little is known about its function in endodormancy regulation. Tree peony (Paeonia suffruticosa), characterized by compound buds and large flowers, is well-known for its ornamental and medicinal value. To break bud dormancy release is a prerequisite of flowering and forcing culture, particularly during the Spring Festival. In this study, the Ca2+ chelator EGTA and Ca2+ channel blocker LaCl3 were applied, resulting in a significant delay in budburst during both chilling- and gibberellin (GA)- induced dormancy release in a dosage-dependent manner. As expected, the retardation of bud break was recovered by the supplementation of 30 mM CaCl2, indicating a facilitating role of calcium in dormancy release. Accordingly, several calcium-sensor-encoding genes including Calmodulin (CaM) and Ca2+-dependent protein kinases (CDPKs) were significantly up-regulated by prolonged chilling and exogenous GAs. Ultrastructure observations revealed a decline in starch grains and the reopening of transport corridors following prolonged chilling. Calcium deposits were abundant in the cell walls and intercellular spaces at the early dormant stage but were enriched in the cytosol and nucleus before dormancy release. Additionally, several genes associated with dormancy release, including EBB1, EBB3, SVP, GA20ox, RGL1, BG6, and BG9, were differentially expressed after calcium blocking and recovery treatments, indicating that calcium might partially modulate dormancy release through GA and ABA pathways. Our findings provide novel insights into the mechanism of dormancy release and offer potential benefits for improving and perfecting forcing culture technology in tree peonies.

Coping Tendency as a Mediator in the Relationship Between Psychological Resilience and Health Problems Among College Students.

Purpose: The study aimed to explore the status of four common health problems (ie, smoking, internet addiction, physical inactivity, psychological disorder) among college students and analyze the relationship between psychological resilience, coping tendency and health problems. Participants and Methods: The convenience sampling method was used to recruit 500 college students from four universities. The General Information Questionnaire, Adolescent Psychological Resilience Scale, Simplified Coping Style Questionnaire and Health Risk Behavior Questionnaire were used for survey. Results: Among the students, there were 71 smokers (15.4%) and 61 internet addicts (13.2%). Over a third of the students reported physical inactivity (35.9%) and a minority had psychological disorder (6.3%). The psychological resilience score differed between students who smoked, had internet addiction, physical inactivity, psychological disorder and those without these health-risk behaviors. Logistic regression analysis showed that negative coping tendency was the common contributing factor of physical inactivity, internet addiction and psychological disorder. Coping tendency played a partial mediating effect in the relationship between psychological resilience and health problems, with a mediating effect of 37.93%. Conclusion: Psychological resilience can not only affect health problems directly but also influence health problems indirectly through coping tendency. Educators and administrators in universities can apply effective measures to improve psychological resilience and positive coping to prevent or reduce health problems among undergraduates.

Tamoxifen Alleviates Endometrial Fibrosis Induced by Anhydrous Ethanol in Rats.

BACKGROUND: As an estrogen receptor modulator, tamoxifen has been utilized in the treatment of fibrotic diseases. However, there is a limited body of research focusing on its potential application in addressing endometrial fibrosis conditions. Our research aims to investigate the effects of tamoxifen at different dosage levels in alleviating endometrial fibrosis and to elucidate its mechanisms of action during the initial stages of endometrial damage. METHODS: A total of thirty sexually mature, unmated female Sprague-Dawley (SD) rats were divided into six distinct groups. To establish the rat uterine adhesion model, the uterine cavity was subjected to perfusion with anhydrous ethanol. The control group received a saline solution, while the treatment group was administered oral estrogen in combination with tamoxifen at doses of 4 mg/kg/d, 20 mg/kg/d, and 40 mg/kg/d. Various techniques, including Hematoxylin and Eosin (HE) staining, Masson's Trichrome staining, Western Blotting analysis, and immunohistochemistry, were employed to assess changes in endometrial thickness, fibrosis, as well as alterations in indicators related to epithelial-mesenchymal transition (EMT), fibrosis, estrogen receptors within the endometrium, and vascular endothelial growth factor (VEGF). RESULTS: In the model group, the levels of endometrial thickness, E-cadherin, Vimentin, estrogen receptor α (ERα), G protein-coupled receptor 30 (GPR30), and VEGF proteins were significantly lower compared to the control group. Conversely, the levels of collagen accumulation, Smooth Muscle Actin (SMA), Transforming Growth Factor ß1 (TGFß1), Drosophila mothers against decapentaplegic protein 2 (Smad2) , and Smad3 were markedly higher than those observed in the control group (p < 0.05, p < 0.01, p < 0.001, p < 0.0001). In contrast, the low-dose tamoxifen group demonstrated significant increases in endometrial thickness, E-cadherin, Vimentin, ERα, GPR30, and VEGF when compared to the model group (p < 0.05, p < 0.01, p < 0.001, p < 0.0001). Moreover, the levels of collagen accumulation, TGFß1, SMA, Smad2, and Smad3, which are indicative of fibrosis and the TGFß1/Drosophila mothers against decapentaplegic (smad) pathway, were notably reduced compared to the model group (p < 0.05, p < 0.0001). CONCLUSIONS: The results of this study suggest that the administration of a low dose (4 mg/kg/d) of tamoxifen in the early stages of endometrial injury may mitigate epithelial-mesenchymal transition (EMT) indicators and reduce fibrosis within the endometrium induced by anhydrous ethanol.

Water pollution scenarios and response options for China.

China has formulated several policies to alleviate the water pollution load, but few studies have quantitatively analyzed their impacts on future water pollution loads in China. Based on grey water footprint (GWF) assessment and scenario simulation, we analyze the water pollution (including COD, NH3-N, TN and TP) in China from 2021 to 2035 under different scenarios for three areas: consumption-side, production-side and terminal treatment. We find that under the current policy scenario, the GWF of COD, NH3-N, TN, and TP in China could be reduced by 15.0 % to 39.9 %; the most effective measures for GWF reduction are diet structure change (in the consumption-side area), and the wastewater treatment rate and livestock manure utilization improvement (in the terminal treatment area). However, the GWF will still increase in 8 provinces, indicating that the current implemented policy is not universally effective in reducing GWF across all provinces. Under the technical improvement scenario, the GWF of the four pollutants will decrease by 54.9 %-71.1 % via improvements in the current measures related to current policies and new measures in the production-side area and the terminal treatment area; thus, GWF reduction is possible in all 31 provinces. However, some policies face significant challenges in achieving full implementation, and certain policies are only applicable to a subset of provinces. Our detailed analysis of future water pollution scenarios and response options to reduce pollution loads can help to inform the protection of freshwater resources in China and quantitatively assess the effectiveness of policies in other fields.

The safety, immunogenicity, and efficacy of heterologous boosting with a SARS-CoV-2 mRNA vaccine (SYS6006) in Chinese participants aged 18 years or more: a randomized, open-label, active-controlled phase 3 trial.

Continuous emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), enhanced transmissibility, significant immune escape, and waning immunity call for booster vaccination. We evaluated the safety, immunogenicity, and efficacy of heterologous booster with a SARS-CoV-2 mRNA vaccine SYS6006 versus an active control vaccine in a randomized, open-label, active-controlled phase 3 trial in healthy adults aged 18 years or more who had received two or three doses of SARS-CoV-2 inactivated vaccine in China. The trial started in December 2022 and lasted for 6 months. The participants were randomized (overall ratio: 3:1) to receive one dose of SYS6006 (N = 2999) or an ancestral receptor binding region-based, alum-adjuvanted recombinant protein SARS-CoV-2 vaccine (N = 1000), including 520 participants in an immunogenicity subgroup. SYS6006 boosting showed good safety profiles with most AEs being grade 1 or 2, and induced robust wild-type and Omicron BA.5 neutralizing antibody response on Days 14 and 28, demonstrating immunogenicity superiority versus the control vaccine and meeting the primary objective. The relative vaccine efficacy against COVID-19 of any severity was 51.6% (95% CI, 35.5-63.7) for any variant, 66.8% (48.6-78.5) for BA.5, and 37.7% (2.4-60.3) for XBB, from Day 7 through Month 6. In the vaccinated and infected hybrid immune participants, the relative vaccine efficacy was 68.4% (31.1-85.5) against COVID-19 of any severity caused by a second infection. All COVID-19 cases were mild. SYS6006 heterologous boosting demonstrated good safety, superior immunogenicity and high efficacy against BA.5-associated COVID-19, and protected against XBB-associated COVID-19, particularly in the hybrid immune population.Trial registration: Chinese Clinical Trial Registry: ChiCTR2200066941.

Long-lasting humoral and cellular memory immunity to vaccinia virus Tiantan provides pre-existing immunity against mpox virus in Chinese population.

Investigating immune memory to vaccinia virus and pre-existing immunity to mpox virus (MPXV) among the population is crucial for the global response to this ongoing mpox epidemic. Blood was sampled from vaccinees inoculated with vaccinia virus Tiantan (VTT) strain born before 1981 and unvaccinated control subjects born since 1982. After at least 40 years of the inoculation, 60% or 5% VTT vaccinees possess neutralizing antibodies (NAbs) to VTT or MPXV, with at least 50% having T cell memory to VTT protein antigens. Notably, 46.7% vaccinees show pre-existing T cell responses to MPXV. Broad pre-existing CD8+ T cell reactivities to MPXV are detected not only against conserved epitopes but also against variant epitopes between VTT and MPXV. Persistent NAbs and T cell memory to VTT among vaccinees, along with pre-existing T cells to MPXV among both vaccinees and the unvaccinated population, indicate a particular immune barrier to mpox.