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During pregnancy, cell senescence at the maternal–fetal interface is required for maternal well-being, placental development, and fetal growth. However, recent reports have shown that aberrant cell senescence is associated with multiple pregnancy-associated abnormalities, such as preeclampsia, fetal growth restrictions, recurrent pregnancy loss, and preterm birth. Therefore, the role and impact of cell senescence during pregnancy requires further comprehension. In this review, we discuss the principal role of cell senescence at the maternal–fetal interface, emphasizing its “bright side” during decidualization, placentation, and parturition. In addition, we highlight the impact of its deregulation and how this “dark side” promotes pregnancy-associated abnormalities. Furthermore, we discuss novel and less invasive therapeutic practices associated with the modulation of cell senescence during pregnancy. Summary Sentence An overview of the recent discoveries on the physiology role of cell senescence in successful pregnancies and pathology role of excessive cell senescence in complicated pregnancy. Graphical Abstract

Senescence occurs earlier in the immune system than in solid organs as age increases. Regulatory T (Treg) cells are among the first cells to exhibit signs of aging. However, whether advanced‐age pregnancy involves Treg cell aging remains unclear. This study demonstrated that the aging of women is accompanied by aging Treg cells and that PD‐1 regulates Treg cell aging. The transfer of young Treg cells can improve the pregnancy outcomes of reproductive‐aged mice by reducing the level of IFN‐γ, a proinflammatory cytokine secreted by Treg cells in aged mice. Transferring α‐PD‐1 mAb‐treated aged Treg cells increases the level of IL‐10, an anti‐inflammatory cytokine secreted by Treg cells in reproductive‐aged mice. Collectively, these findings suggest a potential therapeutic strategy for preventing adverse pregnancy outcomes in older women. Gong et al. first discovered that Treg cells in advanced maternal aged pregnancies exhibited cell senescence as well as functional defects. Moreover, PD‐1 may serve as a novel marker of aged Treg cells. Notably, transferring younger Treg cells or aged Treg cells pretreated with anti‐PD‐1 mAbs improves pregnancy outcomes in aged mouse foster mothers. These findings provide a new strategy for preventing adverse pregnancy outcomes in older women.

Recurrent pregnancy loss (RPL) is a disturbing disease in women, and 50% of RPL is reported to be associated with immune dysfunction. Most previous studies of RPL focused mainly on the relationship between RPL and either T cells or natural killer (NK) cells in peripheral blood and the decidua; few studies presented the systemic profiles of the peripheral immune cell subsets in RPL women. Herein, we simultaneously detected 63 immune cell phenotypes in the peripheral blood from nonpregnant women (NPW), women with a history of normal pregnancy (NP) and women with a history of RPL (RPL) by multi-parameter flow cytometry. The results demonstrated that the percentages of naïve CD4 + T cells, central memory CD4 + T cells, naïve CD8 + T cells, mature NK cells, Vδ1 + T cells and the ratio of Vδ1 + T cells/Vδ2 + T cells were significantly higher in the RPL group than those in the NPW and NP groups, whereas the percentages of terminal differentiated CD4 + T cells, effective memory CD4 + T cells, immature NK cells and Vδ2 + T cells were significantly lower in the RPL group than those in the NPW and NP groups. Interestingly, we found that peripheral T helper (T PH ) cells were more abundant in the NPW group than in the NP and RPL groups. In addition, we also determined the 5 th percentile lower limit and 95 th percentile upper limit of the significantly changed immunological parameters based on the files of the NPW group. Taken together, this is the first study to simultaneously characterize the multiple immune cell subsets in the peripheral blood at a relatively large scale in RPL, which might provide a global readout of the immune status for clinicians to identify clinically-relevant immune disorders and guide them to make clear and individualized advice and treatment plans.

Decidual regulatory T cells (Tregs) are essential for successful pregnancy outcome. A subset of Tregs, T cell immunoglobulin and mucin domain-containing protein 3-positive regulatory T cells (TregsTim-3+), plays a central role in the acceptance of the fetus during early stages of normal pregnancy. The molecular mechanism regulating the differentiation and function of TregsTim-3+ is unknown. Here, we investigated the role of the transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) on decidual TregTim-3+ differentiation. We demonstrated that Blimp-1 enhanced the coexpression of negative costimulatory molecules (Tim-3, T cell immunoreceptor with Ig and ITIM domains, and programmed cell death protein 1) on Tregs and improved their immunosuppressive functions, including increased IL-10 secretion, suppression of effector T cell proliferation, and promotion of macrophage polarization toward the M2 phenotype. Furthermore, we showed that IL-27 regulated the expression of Tim-3 and Blimp-1 through the STAT1 signaling pathway and that transfer of TregsBlimp-1+ into an abortion-prone mouse model effectively reduced embryo absorption rate. We postulated that abnormalities in the IL-27/Blimp-1 axis might be associated with recurrent pregnancy loss (RPL). These findings provided insights for developing more efficient immunotherapies for women with RPL.

Trophoblasts differentiate and form the placenta during pregnancy in a complex and finely orchestrated process, which is dependent on the establishment of maternal-fetal immune tolerance and the proper function of trophoblasts. Trophoblasts express HLA-C and non-classical HLA-Ib molecules (HLA-E, HLA-F, and HLA-G). Numerous studies have shown that the unique expression pattern of the HLA molecules is closely linked to the successful acceptance of allogeneic fetus by the mother during pregnancy. However, some controversies still exist concerning the exact expression and recognition patterns of HLA molecules in different trophoblast subpopulations and cell lines. Thus, we summarize three types of trophoblast subpopulations as well as the common trophoblast lineages. Then, the classification and structural characteristics of HLA molecules were elucidated. Finally, the presence of HLA-C and non-classical HLA-Ib molecules (HLA-E, HLA-F, and HLA-G) in various trophoblasts and cell lines, as well as their potential role in establishing and maintaining normal pregnancy were also discussed. Together, this review will help people comprehensively understand the complex immune interactions between maternal and fetal crosstalk during pregnancy and ultimately better understand the physiological and pathological etiologies of pregnancy.

Background： Atopic dermatitis （AD） is an inflammatory skin disease characterized by chronic recurrent dermatitis with profound itching. Most patients have personal and/or family history of atopic diseases. Several criteria have been proposed for the diagnosis of AD. Although the clinical features of childhood AD have been widely studied, there has been less large-scale study on adult/adolescent AD. The aim of this study was to investigate the clinical features of adult/adolescent patients with chronic symmetrical eczemaJAD and to propose Chinese diagnostic criteria for adult/adolescent AD. Methods： A hospital-based study was performed. Forty-two dermatological centers participated in this study. Adult and adolescent patients （12 years and over） with chronic symmetrical eczema or AD were included in this study. Questionnaires were completed by both patients and-investigators. The valid questionnaires were analyzed using EpiData 3.1 and SPSS 17.0 software. Results： A total of 2662 valid questionnaires were collected （1369 male and 1293 female）. Of all 2662 patients, 2062 （77.5%） patients had the disease after 12 years old, while only 600 （22.5%） patients had the disease before 12 years old, suggesting late-onset eczema/AD is common. Two thousand one hundred and thirty-nine （80.4%） patients had the disease for more than 6 months. One thousand one hundred and forty-four （43.0%） patients had a personal and/or family history of atopic diseases. One thousand five hundred and forty-eight （58.2%） patients had an elevated total serum IgE and/or eosinophilia and/or positive allergen-specific IgE. Based on these clinical and laboratory features, we proposed Chinese criteria for adult/adolescent AD. Of all 2662 patients, 60.3% were satisfied with our criteria, while only 48.2% satisfied with Hanifin Rajka criteria and 32.7% satisfied with Williams criteria, suggesting a good sensitivity of our criteria in adult/adolescent AD patients. Conclusion： Late-onset of eczema or AD is common. The clinical manifestations of AD are heterogeneous. We have proposed Chinese diagnostic criteria for adolescent and adult AD, which are simple and sensitive for diagnosis of adult/adolescent AD.

Objectives Cryptococcus heimaeyensis S20 is found in Antarctica and can produce exopolysaccharides (CHEPS). Here, we explore the anti‐tumour effects of CHEPS on non‐small cell lung cancer (NSCLC). Materials and methods Cell viability was assessed by CCK8 and colony formation assays. Flow cytometry was used to analyse the cell cycle, cell apoptosis and reactive oxygen species (ROS). Cell autophagy was detected by EGFP‐LC3 puncta assay, Lyso‐Tracker Red staining and transmission electron microscopy. mRNA and protein levels were analysed by qRT‐PCR and Western blot. Related mechanisms were confirmed using appropriate inhibitors or shRNA. In vitro results were further confirmed by a tumour xenograft study. Results CHEPS inhibited the proliferation of NSCLC cells by inducing S‐ and G2/M‐phase arrest and autophagic cell death, but not apoptosis. CHEPS was less toxic to normal human embryonic lung fibroblasts. CHEPS activated the MAPK pathway in NSCLC cells, and p38 and ERK promoted CHEPS‐induced cell death. Further studies showed that p38 and ERK promoted CHEPS‐induced NSCLC cell autophagy and ERK promoted CHEPS‐induced S‐ and G2/M‐phase arrest. ROS were induced by CHEPS. A ROS scavenger attenuated CHEPS‐induced p38 and ERK activation, autophagy and cell death. Finally, CHEPS reduced orthotopic lung tumour growth without organ‐related toxicity. CHEPS also induced ROS, activated p38 and ERK, and triggered autophagy in vivo. Conclusions CHEPS induces autophagic cell death and S‐ and G2/M‐phase arrest in NSCLC cells via ROS/p38 and ROS/ERK signalling. Cryptococcus heimaeyensis S20 is found in Antarctica and can produce exopolysaccharides (CHEPS). Hao et al demonstrate that CHEPS induces reactive oxygen species (ROS) generation, which activates p38 and ERK, leading to cell autophagy and death in non‐small cell lung cancer (NSCLC) cells. CHEPS‐activated ERK also induces S‐ and G2/M‐phase arrest.

Nephrotic syndrome (NS) is still a therapeutic challenge. To date there is no ideal treatment. Evidence suggest that multidrug therapy has more effect than monotherapy in amelioration of renal injury. Salvianolic acid A (SAA) is the major active component of Salviae Miltio2rrhizae Bunge. Previous studies have demonstrated that SAA is a multi-target agent and has various pharmacological activities. The pleiotropic properties of SAA predict its potential in the treatment of NS. The study investigated the effect of SAA on doxorubicin-induced nephropathy. The kidney function related-biochemical changes, hemorheological parameters and oxidative stress status were determined and histological examination using light and transmission electron microcopies and western blot analysis were also performed. Results revealed that treatment with SAA alleviated histological damages, relieved proteinuria, hypoalbuminemia and hyperlipidemia, reduced oxidative stress, as well as improving hemorheology. Furthermore, SAA restored podocin expression, down-regulated the expression of NF-κB p65 and p-IκBα while up-regulating IκBα protein expression. Overall, as a multifunctional agent, SAA has a favorable renoprotection in doxorubicin-induced nephropathy. The anti-inflammation, antioxidant, amelioration of podocyte injury, improvement of hemorheology and hypolipidemic properties may constituent an important part of its therapeutic effects. All these indicate that SAA is likely to be a promising agent for NS.

Peritoneal metastasis (PM), the regional progression of intra-abdominal malignancies, is a common sequelae of colorectal cancer (CRC). Immunotherapy is slated to be effective in generating long-lasting anti-tumour response as it utilizes the specificity and memory of the immune system. In the tumour microenvironment, tumour associated macrophages (TAMs) are posited to create an anti-inflammatory pro-tumorigenic environment. In this paper, we aimed to identify immunomodulatory factors associated with colorectal PM (CPM). A publicly available colorectal single cell database (GSE183916) was analysed to identify possible immunological markers that are associated with the activation of macrophages in cancers. Immunohistochemical analysis for V-set and immunoglobin containing domain 4 (VSIG4) expression was performed on tumour microarrays (TMAs) of tumours of colorectal origin (n = 211). Expression of VSIG4 in cell-free ascites obtained from CPM patients ( n  = 39) was determined using enzyme-linked immunosorbent assay (ELISA). CD163-positive TAMs cluster expression was extracted from a publicly available single cell database and evaluated for the top 100 genes. From these macrophage-expressed genes, VSIG4, a membrane protein produced by the M2 macrophages, mediates the up-regulation of anti-inflammatory and down-regulation of pro-inflammatory macrophages, contributing to an overall anti-inflammatory state. CRC TMA IHC staining showed that low expression of VSIG4 in stromal tissues of primary CRC are associated with poor prognosis (p = 0.0226). CPM ascites also contained varying concentrations of VSIG4, which points to a possible role of VSIG4 in the ascites. The contribution of VSIG4 to CPM development can be further evaluated for its potential as an immunotherapeutic agent.

Inflammasome is linked to many inflammatory diseases, including COVID-19 and autoimmune liver diseases. While severe COVID-19 was reported to exacerbate liver failure, we report a fatal acute-on-chronic liver failure (ACLF) in a stable primary biliary cholangitis-autoimmune hepatitis overlap syndrome patient triggered by a mild COVID-19 infection. Postmortem liver biopsy showed sparse SARS-CoV-2-infected macrophages with extensive ASC (apoptosis-associated speck-like protein containing a CARD) speck-positive hepatocytes, correlating with elevated circulating ASC specks and inflammatory cytokines, and depleted blood monocyte subsets, indicating widespread liver inflammasome activation. This first report of a fatal inflammatory cascade in an autoimmune liver disease triggered by a mild remote viral infection hopes to elucidate a less-described pathophysiology of ACLF that could prompt consideration of new diagnostic and therapeutic options.