MaiJiTong granule attenuates atherosclerosis by reducing ferroptosis via activating STAT6-mediated inhibition of DMT1 and SOCS1/p53 pathways in LDLR-/- mice.

BACKGROUND AND PURPOSE: Atherosclerosis is the primary pathological basis of cardiovascular disease. Ferroptosis is a regulated form of cell death, a process of lipid peroxidation driven by iron, which can initiate and promote atherosclerosis. STAT6 is a signal transducer that shows a potential role in regulating ferroptosis, but, the exact role in ferroptosis during atherogenesis remains unclear. The Traditional Chinese Medicine Maijitong granule (MJT) is used for treating cardiovascular disease and shows a potential inhibitory effect on ferroptosis. However, the antiatherogenic effect and the underlying mechanism remain unclear. In this study, we determined the role of STAT6 in ferroptosis during atherogenesis, investigated the antiatherogenic effect of MJT, and determined whether its antiatherogenic effect was dependent on the inhibition of ferroptosis. METHODS: 8-week-old male LDLR-/- mice were fed a high-fat diet (HFD) at 1st and 10th week, respectively, to assess the preventive and therapeutic effects of MJT on atherosclerosis and ferroptosis. Simultaneously, the anti-ferroptotic effects and mechanism of MJT were determined by evaluating the expression of genes responsible for lipid peroxidation and iron metabolism. Subsequently, we reanalyzed microarray data in the GSE28117 obtained from cells after STAT6 knockdown or overexpression and analyzed the correlation between STAT6 and ferroptosis. Finally, the STAT6-/- mice were fed HFD and injected with AAV-PCSK9 to validate the role of STAT6 in ferroptosis during atherogenesis and revealed the antiatherogenic and anti-ferroptotic effect of MJT. RESULTS: MJT attenuated atherosclerosis by reducing plaque lesion area and enhancing plaque stability in both preventive and therapeutic groups. MJT reduced inflammation via suppressing inflammatory cytokines and inhibited foam cell formation by lowering the LDL level and promoting ABCA1/G1-mediated lipid efflux. MJT ameliorated the ferroptosis by reducing lipid peroxidation and iron dysregulation during atherogenesis. Mechanistically, STAT6 negatively regulated ferroptosis by transcriptionally suppressing SOCS1/p53 and DMT1 pathways. MJT suppressed the DMT1 and SOCS1/p53 via stimulating STAT6 phosphorylation. In addition, STAT6 knockout exacerbated atherosclerosis and ferroptosis, which abolished the antiatherogenic and anti-ferroptotic effects of MJT. CONCLUSION: STAT6 acts as a negative regulator of ferroptosis and atherosclerosis via transcriptionally suppressing DMT1 and SOCS1 expression and MJT attenuates atherosclerosis and ferroptosis by activating the STAT6-mediated inhibition of DMT1 and SOCS1/p53 pathways, which indicated that STAT6 acts a novel promising therapeutic target to ameliorate atherosclerosis by inhibiting ferroptosis and MJT can serve as a new therapy for atherosclerosis treatment.

Human leukocyte antigen-G in gynaecological tumours.

Gynaecological tumours that threaten the health of women, especially when advanced and recurrent, have remained mostly intractable to existing treatments. Therefore, new therapeutic targets are urgently needed. Human leukocyte antigen-G (HLA-G) is a nonclassical major histocompatibility complex class I molecule typically expressed in foetuses for protection against destruction by the maternal immune system. HLA-G is also expressed under pathological conditions, such as in solid tumours, and may participate in tumour development and serve as a novel immune checkpoint in cancer. Furthermore, it is expressed in most gynaecological tumours. Therefore, inhibiting HLA-G and its receptors to block the immune escape pathway could represent a new strategy in cancer immunotherapy. To the best of our knowledge, this review is the first to summarize recent research findings on HLA-G in gynaecological oncology. We highlight the fact that HLA-G is expressed in gynaecological tumour tissues, wherein it inactivates immune effectors involved in tumour progression. Further studies on HLA-G in gynaecological oncology are needed to incorporate HLA-G into the design and evaluation of immunotherapy for malignant gynaecological diseases.

Follicular helper T lymphocytes in the endometria of patients with reproductive failure: Association with pregnancy outcomes and inflammatory status of the endometria.

PROBLEM: The phenotypes and functions of B and CD4+ T-helper cell subsets during chronic inflammation of the endometria remain largely unexplored. This study aimed to investigate the characteristics and functions of follicular helper T (Tfh) cells to understand the pathological mechanisms of chronic endometritis (CE). METHOD OF STUDY: Eighty patients who underwent hysteroscopic and histopathological examinations for CE were divided into three groups-those with positive results for hysteroscopy and CD138 staining (DP), negative results for hysteroscopy but positive CD138 staining (SP), and negative results for hysteroscopy and CD138 staining (DN). The phenotypes of B cells and CD4+ T-cell subsets were analyzed using flow cytometry. RESULTS: CD38+ and CD138+ cells were mainly expressed in the non-leukocyte population of the endometria, and the endometrial CD19+ CD138+ B cells were fewer than the CD3+ CD138+ T cells. The percentage of Tfh cells increased with chronic inflammation in the endometria. Additionally, the elevated percentage of Tfh cells correlated with the number of miscarriages. CONCLUSIONS: CD4+ T cells, particularly Tfh cells, may be critical in chronic endometrial inflammation and affect its microenvironment, thereby regulating endometrial receptivity, compared to B cells.

Outcomes associated with different surgical approaches to radical hysterectomy: A systematic review and network meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of five different approaches to cervical cancer surgery. METHODS: We conducted a systematic search for comparative studies on different radical hysterectomy types for cervical cancer in PubMed, Embase, the Cochrane Library, and Web of Science databases. All included observational studies used survival analyses to compare clinical outcomes of patients undergoing different radical hysterectomy types. All studies were assessed by the Newcastle-Ottawa Scale with scores of at least seven points. We extracted the relevant data and conducted a network meta-analysis to compare clinical outcomes among five surgical approaches. RESULTS: Thirty studies (n = 11 353) were included. Robotic surgery had the lowest blood loss volume and hospitalization duration; open surgery had the shortest operative time. Vaginal assisted laparoscopic surgery was associated with the highest number of resected lymph nodes and lowest rate of perioperative complications. Survival outcomes and tumor recurrence outcomes were similar among the approaches. CONCLUSION: The current approaches to cervical cancer surgery have comparable efficacies.

Transcriptomic analysis of mid-secretory endometrium reveals essential immune factors associated with pregnancy after single euploid blastocyst transfer.

PURPOSE: Implantation is a limiting factor for treatment success in assisted reproduction. Both embryonic and endometrial factors contribute to implantation. Embryonic factors have often been ignored in previous studies about the role of endometrium in implantation. In this study, we sought to identify the endometrial genes associated with negative pregnancy outcomes following the transfer of a single euploid blastocyst. METHODS: Computational analyses of the transcriptomes of mid-secretory endometria from nine pregnant and seven non-pregnant patients in a cycle preceding the transfer of a single euploid blastocyst in a vitrified-warmed cycle were performed. RESULTS: Principal component analysis of two reported endometrial receptivity gene sets showed close clustering of the pregnant and non-pregnant samples. Differential gene expression analysis and co-expression module analysis identified 131 genes associated with the pregnancy status. The endometrial signatures identified highlight the importance of immune and metabolic regulation in pregnancy outcome. Network analysis identified 20 hub genes that could predict pregnancy outcomes with 88.9% sensitivity and 85.7% specificity. Single-cell gene expression analysis highlighted the regulation of endometrial natural killer (NK) cells, T cells, and macrophages during embryo implantation. Immune cell abundance analysis supported the dysregulation of cytotoxic immune cells in the endometria of non-pregnant women. CONCLUSIONS: We reported the first endometrial gene signature associated with pregnancy after elimination of embryo aneuploidy and highlighted the importance of the endometrial immune microenvironment and metabolic status in pregnancy outcomes.

Single-cell Sequencing Reveals Clearance of Blastula Chromosomal Mosaicism in In Vitro Fertilization Babies.

Although chromosomal mosaic embryos detected by trophectoderm (TE) biopsy offer healthy embryos available for transfer, high-resolution postnatal karyotyping and chromosome testing of the transferred embryos are insufficient. Here, we applied single-cell multi-omics sequencing for seven infants with blastula chromosomal mosaicism detected by TE biopsy. The chromosome ploidy was examined by single-cell genome analysis, with the cellular identity being identified by single-cell transcriptome analysis. A total of 1616 peripheral leukocytes from seven infants with embryonic chromosomal mosaicism and three control ones with euploid TE biopsy were analyzed. A small number of blood cells showed copy number alterations (CNAs) on seemingly random locations at a frequency of 0%-2.5% per infant. However, none of the cells showed CNAs that were the same as those of the corresponding TE biopsies. The blastula chromosomal mosaicism may be fully self-corrected, probably through the selective loss of the aneuploid cells during development, and the transferred embryos can be born as euploid infants without mosaic CNAs corresponding to the TE biopsies. The results provide a new reference for the evaluations of transferring chromosomal mosaic embryos in certain situations.

Eukaryotic translation factor eIF5A contributes to acetic acid tolerance in Saccharomyces cerevisiae via transcriptional factor Ume6p.

BACKGROUND: Saccharomyces cerevisiae is well-known as an ideal model system for basic research and important industrial microorganism for biotechnological applications. Acetic acid is an important growth inhibitor that has deleterious effects on both the growth and fermentation performance of yeast cells. Comprehensive understanding of the mechanisms underlying S. cerevisiae adaptive response to acetic acid is always a focus and indispensable for development of robust industrial strains. eIF5A is a specific translation factor that is especially required for the formation of peptide bond between certain residues including proline regarded as poor substrates for slow peptide bond formation. Decrease of eIF5A activity resulted in temperature-sensitive phenotype of yeast, while up-regulation of eIF5A protected transgenic Arabidopsis against high temperature, oxidative or osmotic stress. However, the exact roles and functional mechanisms of eIF5A in stress response are as yet largely unknown. RESULTS: In this research, we compared cell growth between the eIF5A overexpressing and the control S. cerevisiae strains under various stressed conditions. Improvement of acetic acid tolerance by enhanced eIF5A activity was observed all in spot assay, growth profiles and survival assay. eIF5A prompts the synthesis of Ume6p, a pleiotropic transcriptional factor containing polyproline motifs, mainly in a translational related way. As a consequence, BEM4, BUD21 and IME4, the direct targets of Ume6p, were up-regulated in eIF5A overexpressing strain, especially under acetic acid stress. Overexpression of UME6 results in similar profiles of cell growth and target genes transcription to eIF5A overexpression, confirming the role of Ume6p and its association between eIF5A and acetic acid tolerance. CONCLUSION: Translation factor eIF5A protects yeast cells against acetic acid challenge by the eIF5A-Ume6p-Bud21p/Ime4p/Bem4p axles, which provides new insights into the molecular mechanisms underlying the adaptive response and tolerance to acetic acid in S. cerevisiae and novel targets for construction of robust industrial strains.

A modified suspension test for estimating the mutagenicity of samples containing free and (or) protein-bound histidine.

The Ames test has not been very effective in estimating the mutagenicity of histidine-containing samples because external free and (or) protein-bound histidine in these samples would allow the histidine auxotrophs in such test samples to grow more compared with the negative controls that were used as the reference. This could give rise to a false positive.n this study, a modified suspension mutagenicity assay (MS assay) was developed. The tester strains were incubated in Luria-Bertani (LB) broth containing different concentrations of traditional Chinese medicines (TCMs) until the declining phase, and the test samples were assayed to be mutagenic or not by observing whether statistically significant differences were demonstrated in the relative reversion frequencies (RRFs) between the negative control groups and the test groups. Collectively, using LB broth as the test medium and comparing the RRFs in the declining phase made this assay less influenced by the presence of histidine in the test samples.The mutagenicity of some TCMs was measured with the MS assay. The results in MS assay were consistent with those in the mammalian bone marrow chromosomal aberration test, which indicated that the MS assay was appropriate to estimate the mutagenicity of samples containing free and (or) protein-bound histidine.