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Iron has been shown to trigger oxidative stress by elevating reactive oxygen species (ROS) and to participate in different modes of cell death, such as ferroptosis, apoptosis and necroptosis. However, whether iron-elevated ROS is also linked to pyroptosis has not been reported. Here, we demonstrate that iron-activated ROS can induce pyroptosis via a Tom20-Bax-caspase-GSDME pathway. In melanoma cells, iron enhanced ROS signaling initiated by CCCP, causing the oxidation and oligomerization of the mitochondrial outer membrane protein Tom20. Bax is recruited to mitochondria by oxidized Tom20, which facilitates cytochrome c release to cytosol to activate caspase-3, eventually triggering pyroptotic death by inducing GSDME cleavage. Therefore, ROS acts as a causative factor and Tom20 senses ROS signaling for iron-driven pyroptotic death of melanoma cells. Since iron activates ROS for GSDME-dependent pyroptosis induction and melanoma cells specifically express a high level of GSDME, iron may be a potential candidate for melanoma therapy. Based on the functional mechanism of iron shown above, we further demonstrate that iron supplementation at a dosage used in iron-deficient patients is sufficient to maximize the anti-tumor effect of clinical ROS-inducing drugs to inhibit xenograft tumor growth and metastasis of melanoma cells through GSDME-dependent pyroptosis. Moreover, no obvious side effects are observed in the normal tissues and organs of mice during the combined treatment of clinical drugs and iron. This study not only identifies iron as a sensitizer amplifying ROS signaling to drive pyroptosis, but also implicates a novel iron-based intervention strategy for melanoma therapy.

Pyroptosis is a form of regulated cell death mediated by gasdermin family members, among which the function of GSDMC has not been clearly described. Herein, we demonstrate that the metabolite α-ketoglutarate (α-KG) induces pyroptosis through caspase-8-mediated cleavage of GSDMC. Treatment with DM-αKG, a cell-permeable derivative of α-KG, elevates ROS levels, which leads to oxidation of the plasma membrane-localized death receptor DR6. Oxidation of DR6 triggers its endocytosis, and then recruits both pro-caspase-8 and GSDMC to a DR6 receptosome through protein-protein interactions. The DR6 receptosome herein provides a platform for the cleavage of GSDMC by active caspase-8, thereby leading to pyroptosis. Moreover, this α-KG-induced pyroptosis could inhibit tumor growth and metastasis in mouse models. Interestingly, the efficiency of α-KG in inducing pyroptosis relies on an acidic environment in which α-KG is reduced by MDH1 and converted to L-2HG that further boosts ROS levels. Treatment with lactic acid, the end product of glycolysis, builds an improved acidic environment to facilitate more production of L-2HG, which makes the originally pyroptosis-resistant cancer cells more susceptible to α-KG-induced pyroptosis. This study not only illustrates a pyroptotic pathway linked with metabolites but also identifies an unreported principal axis extending from ROS-initiated DR6 endocytosis to caspase-8-mediated cleavage of GSDMC for potential clinical application in tumor therapy.

Sesquiterpenes constitute the principal components of the genus Ainsliaea, encompassing guaiane, germacrane, eudesmane, and polymer sesquiterpene lactones types. These secondary metabolites exhibit diverse pharmacological activities, including antitumor, antibacterial, anti-inflammatory, antiviral, antioxidant, hepatoprotective, and neuroprotective effects. Through a comprehensive literature search of the Web of Science, PubMed, SciFinder, and CNKI databases, it was discovered that there are as many as 145 main sesquiterpenoids in the genus Ainsliaea. However, the nuclear magnetic resonance (NMR) data for the sesquiterpenes in this genus have not been systematically compiled and summarized. Therefore, this review aims to highlight the chemical structures, NMR data, and pharmacological activities of sesquiterpenes in Ainsliaea. By meticulously analyzing published scholarly literature, our goal is to provide a solid foundation for further exploration of new sesquiterpenes and extensive utilization of this genus.

The mucosa of vertebrates is a particularly complex but dynamic environment in which the host constantly interacts with trillions of commensal microorganisms and pathogens. Although the internal and external mucosal microbiomes with immune defense of mammals have been well investigated, the relationship between mucosal microbes and their host’s immune responses has not been systematically understood in the early vertebrates. In this study, we compared the composition and distribution of mucosal microbiota in common carp ( Cyprinus carpio ), and found that there were significant differences of microbiota between in the internal (gut) and external mucosal (buccal mucosa, gills and skin) tissues. Next, we successfully constructed an infection model with spring viremia of carp virus (SVCV). Specifically, following viral infection, the immune and antiviral related genes showed different up-regulation in all selected mucosal tissues while significant morphological changes were only found in external tissues including buccal mucosa, gills and skin. Using 16S rRNA gene sequence, we revealed that the abundance of Proteobacteria in mucosal tissues including buccal mucosa, gills and gut showed increased trend after viral infection, whereas the abundance of Fusobacteria significantly decreased in gut. In addition, the loss of dominant commensal microorganisms and increased colonization of opportunistic bacteria were discovered in the mucosal surfaces indicating that a secondary bacterial infection might occur in these mucosal tissues after viral infection. Overall, our results firstly point out the distribution of internal and external mucosal microbiota and analyze the changes of mucosal microbiota in common carp after SVCV infection, which may indicated that the potential role of mucosal microbiota in the antiviral process in early vertebrates.

With the acceleration of urbanization, the surge in urban population led to disorder in urban characteristics and appearance, triggering a conflict between Xiangchou and rapid urbanization. This study selected Xiaoyaojin Park in Hefei as a case study and, based on Kevin Lynch’s “Image of the City” theory, divided urban spatial elements into five categories: Paths, Edges, Districts, Nodes, and Landmarks. By using eye-tracking technology, this study compared and analyzed the visual preferences of local students in Hefei (Xiangchou) and non-local students (non-Xiangchou) for urban elements, and explored the elements that carried Xiangchou through semi-structured interviews. This research found that there were significant differences in visual behavior between the two groups, with the non-Xiangchou group spending more time looking at edge elements, while the Xiangchou group showed more pronounced visual differences concerning Landmarks and Nodes. Nevertheless, Landmarks served as an important carrier of Xiangchou for both groups. The findings provide a new perspective on urban renewal and transformation, emphasizing the need to start from the emotions of residents, and to embed or preserve urban memory points, in order to enhance urban recognizability.

Objective To investigate the effects of different drug treatments on uterine artery blood flow parameters, serum placental growth factor (PLGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and sFlt-1/PLGF in patients with recurrent spontaneous abortion and to explore the predictive value of uterine artery blood flow parameters, serum PLGF, sFlt-1, and sFlt-1/PLGF for pregnancy outcomes. Methods This retrospective cohort study included 173 patients who experienced recurrent spontaneous abortion and 100 control patients. Patients with recurrent spontaneous abortion were divided into an aspirin group (75 patients), aspirin combined with low molecular weight heparin (LMWH) group (68 patients), and non-drug group (30 patients) based on different drug treatments. Uterine artery blood flow parameters at gestational weeks 30-31 +6 were monitored for the four groups, and serum samples were collected at gestational weeks 30-31 +6 to measure the levels of serum PLGF and sFlt-1 and calculate the sFlt-1/PLGF ratio. Results 1. Uterine artery blood flow parameters at gestational weeks 30-31 +6 were significantly greater in the non-drug group than in the aspirin group, combined drug group, and control group ( p <0.05). 2. Serum PLGF levels and the sFlt-1/PLGF ratio at gestational weeks 30-31 +6 were significantly lower in the non-drug group than in the aspirin group, combined drug group, and control group, while serum sFlt-1 levels were significantly greater in the non-drug group than in the aspirin group, combined drug group, and control group ( p <0.05). 3. Serum PLGF, sFlt-1, and sFlt-1/PLGF had lower diagnostic efficiency for predicting hypertensive disorders during pregnancy than the combined diagnostic efficiency of serum PLGF, sFlt-1, and sFlt-1/PLGF with uterine artery blood flow parameters at gestational weeks 30-31 +6 . Conclusion Aspirin and aspirin combined with LMWH can upregulate serum PLGF and decrease serum sFlt-1 levels in patients with recurrent spontaneous abortion, reduce the miscarriage rate, and significantly improve pregnancy outcomes. The combination of serum PLGF, sFlt-1, sFlt-1/PLGF, and uterine artery blood flow parameters can effectively predict hypertensive disorders during pregnancy.

Background Virescent mutation broadly exists in plants and is an ideal experimental material to investigate regulatory mechanisms underlying chlorophyll synthesis, photosynthesis and plant growth. Up to date, the molecular mechanisms in two virescent mutations have been clarified in cottons ( Gossypiuma hirsutum ). A virescent mutation has been found in the cotton strain Sumian 22, and the underlying molecular mechanisms have been studied. Methods The virescent mutant and wild type (WT) of Sumian 22 were cross-bred, and the F 1 population were self-pollinated to calculate the segregation ratio. Green and yellow leaves from F 2 populations were subjected to genome sequencing and bulked-segregant analysis was performed to screen mutations. Real-time quantitative PCR (RT-qPCR) were performed to identify genes in relations to chlorophyll synthesis. Intermediate products for chlorophyll synthesis were determined to validate the RT-qPCR results. Results The segregation ratio of green and virescent plants in F2 population complied with 3:1. Compared with WT, a 0.34 Mb highly mutated interval was identified on the chromosome D10 in mutant, which contained 31 genes. Among them, only ABCI1 displayed significantly lower levels in mutant than in WT. Meanwhile, the contents of Mg-protoporphyrin IX, protochlorophyllide, chlorophyll a and b were all significantly lower in mutant than in WT, which were consistent with the inhibited levels of ABCI1 . In addition, a mutation from A to T at the -317 bp position from the start codon of ABCI1 was observed in the genome sequence of mutant. Conclusions Inhibited transcription of ABCI1 might be the mechanism causing virescent mutation in Sumian 22 cotton, which reduced the transportation of protoporphyrin IX to plastid, and then inhibited Mg-protoporphyrin IX, Protochlorophyllide and finally chlorophyll synthesis. These results provided novel insights into the molecular mechanisms underlying virescent mutation in cotton.

Background Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder associated with pregnancy and is usually diagnosed based on high serum bile acid. However, the pathogenesis of ICP is unclear. Ferroptosis has been reported as an iron-dependent mechanism of cell death. Although the role of Ferritin Heavy Chain 1 (FTH1) in ferroptosis has been extensively studied in various diseases, its mechanism in ICP through ferroptosis is yet to be analyzed. Methods Placental tissues from patients with ICP and healthy controls were employed to verify the expression of FTH1. Taurocholic acid (TCA)-induced HTR-8/SVneo cells were established as an in vitro model for ICP, and ferroptosis-related experiments were performed. In particular, HTR-8/SVneo cells with or without overexpressing FTH1 and HTR-8/SVneo cells with or without TCA induction were investigated to explore the relationship between FTH1 and ferroptosis during ICP in vitro, respectively. Results FTH1 was significantly downregulated in the ICP group compared with the control group. Furthermore, FTH1 and ferroptosis-related protein levels were downregulated, while the intracellular iron, reactive oxygen species, and lipid peroxidation levels were upregulated in the TCA-induced HTR-8/SVneo cells. In contrast, ferroptosis was inhibited by overexpression of FTH1 in TCA-induced HTR-8/SVneo cells. Conclusions A high concentration of TCA in HTR-8/SVneo cells decreased the expression of FTH1. Overexpression of FTH1 could prevent cell death from ferroptosis induced by TCA. Thus, inhibiting the downregulation of FTH1 could be a potential therapeutic target for ICP treatment.

Objective. This study aimed to explore the specific pathways by which HOX transcript antisense intergenic RNA contributes to the pathogenesis of unexplained recurrent spontaneous abortion. Methods. Real-time quantitative PCR was employed to assess the differential expression levels of HOX transcript antisense intergenic RNA in chorionic villi tissues from unexplained recurrent spontaneous abortion patients and women with voluntarily terminated pregnancies. HTR-8/SVneo served as a cellular model. Knockdown and overexpression of HOX transcript antisense intergenic RNA in the cells were achieved through siRNA transfection and pcDNA3.1 transfection, respectively. Cell viability, migration, and invasion were evaluated using cell counting kit-8, scratch, and Transwell assays, respectively. The interaction among the HOX transcript antisense intergenic RNA /miR-1277-5p/fibrillin 2 axis was predicted through bioinformatics analysis and confirmed through in vitro experiments. Furthermore, the regulatory effects of the HOX transcript antisense intergenic RNA /miR-1277-5p/fibrillin 2 signaling axis on cellular behaviors were validated in HTR-8/SVneo cells. Results. We found that HOX transcript antisense intergenic RNA was downregulated in chorionic villi tissues from unexplained recurrent spontaneous abortion patients. Overexpression of HOX transcript antisense intergenic RNA significantly enhanced the viability, migration, and invasion of HTR-8/SVneo cells, while knockdown of HOX transcript antisense intergenic RNA had the opposite effects. We further confirmed the regulatory effect of the HOX transcript antisense intergenic RNA /miR-1277-5p/fibrillin 2 signaling axis in unexplained recurrent spontaneous abortion. Specifically, HOX transcript antisense intergenic RNA and fibrillin 2 were found to reduce the risk of unexplained recurrent spontaneous abortion by enhancing cell viability, migration, and invasion, whereas miR-1277-5p exerted the opposite effects. Conclusion. HOX transcript antisense intergenic RNA promotes unexplained recurrent spontaneous abortion development by targeting inhibition of miR-1277-5p/fibrillin 2 axis. Summary Sentence HOTAIR and FBN2 reduced the risk of URSA by enhancing cell viability, migration, and invasion, while miR-1277-5p exerted the opposite effects. Graphical Abstract Villus tissues from unexplained recurrent spontaneous abortion patients (unexplained recurrent spontaneous abortion group, n = 47) and women with voluntary termination of pregnancy (Normal group, n = 47) were collected. lncRNA- HOX transcript antisense intergenic RNA siRNA, pcDNA3.1-lncRNA- HOX transcript antisense intergenic RNA, miR-1277-5p inhibitor, miR-1277-5p mimics, and si-fibrillin 2 were transfected into human trophoblast HTR-8/SVneo. Real-time quantitative PCR was used to detect the level of lncRNA HOX transcript antisense intergenic RNA. Then cell counting kit-8 assay, scratch assay, and Transwell assay were used to detect cell viability, migration ability, and invasion ability. The interaction between HOX transcript antisense intergenic RNA and miR-1277-5p, as well as between miR-1277-5p and fibrillin 2, was determined by bioinformatics prediction and Dual-luciferase reporter assay. Our research results indicate that HOX transcript antisense intergenic RNA was downregulated in chorionic villi tissues from unexplained recurrent spontaneous abortion patients. Overexpression of HOX transcript antisense intergenic RNA significantly enhanced the viability, migration, and invasion of HTR-8/SVneo cells, while knockdown of HOX transcript antisense intergenic RNA had the opposite effects. We further confirmed the regulatory effect of the HOX transcript antisense intergenic RNA /miR-1277-5p/fibrillin 2 signaling axis in unexplained recurrent spontaneous abortion. Specifically, HOX transcript antisense intergenic RNA and fibrillin 2 were found to reduce the risk of unexplained recurrent spontaneous abortion by enhancing cell viability, migration, and invasion, whereas miR-1277-5p exerted the opposite effects.

Background Metabolic syndrome has become a major health threat throughout the world, but there are few studies that focus on the effects of housework on human metabolism. This study explores the association between housework and metabolic markers and examines whether there are gender differences in the relationship of housework intensity on these markers. Methods We obtained data for 2,624 participants from the China Health and Nutrition Survey and used binary logistic regression to analyze the association between housework and metabolic markers (triglycerides, high- and low-density lipoprotein cholesterol, hemoglobin, blood glucose, cholesterol, and blood pressure). Results We observed no association between housework and metabolic markers for men. However, we find that women who engaged in housework had a higher risk of triglycerides than those who did not (OR=1.16, 95% CI: 1.16, 4.25). Compared with low-intensity, we also find that women who performed moderate- and high-housework intensity had a higher risk of triglycerides (moderate-intensity: OR=1.78, 95% CI: 1.14, 2.78; high-intensity: OR=1.91, 95% CI: 1.22, 2.98), MetS (OR=1.54, 95% CI: 0.98, 2.43; OR=1.68, 95% CI: 1.07, 2.66), pre-hypertension (OR=1.68, 95% CI: 1.08, 2.62; OR=1.63, 95% CI: 1.04, 2.55), and obesity (OR=1.65, 95% CI: 1.01, 2.70; OR=1.66, 95% CI: 1.01, 2.72). Conclusion In women, we find that housework is positively associated with the metabolic markers, triglycerides, MetS, and pre-hypertension. However, we did not find evidence that this relationship exists in men, f or any biomarkers we considered. One possible explanation is that people who engage in high-intensity housework are more stressed and sleep less, which could be a mechanism by which housework becomes associated with metabolic disease.