Demystifying the landscape of endometrial immune microenvironment in luteal-phase from cuprotosis: Implications for the mechanism and treatment of RPL.

BACKGROUND: Adaptive changes in the endometrial immune microenvironment during the luteal phase are essential for pregnancy, and their abnormalities are associated with recurrent pregnancy loss (RPL). Nevertheless, the specific mechanism is still unknown. Cuprotosis, an innovatively discovered type of programmed cell death, provides us with a pioneering perspective to decipher the landscape of luteal-phase endometrial immune microenvironment in RPL. This study aimed to analyze the immune landscape of luteal-phase endometrial microenvironment in RPL and explore the association of cuprotosis with it through integrative bioinformatics analysis. METHODS: The microarrays involving the luteal phase endometrial tissue of RPL were obtained from the GEO database. Differentially expressed genes (DEGs) of RPL were screened and key modules were detected by WGCNA. GO, KEGG, and GSEA immune enrichment analyses were performed on the DEGs in the most relevant modules to RPL. Then, the endometrial immune microenvironment landscape of RPL was analyzed, including immune infiltration analysis and correlation analysis between immune cells or immune functions. The interaction of cuprotosis-related genes (CRGs), the expression level between groups, the immune localization and their correlation with immune cells and immune function were analyzed. LASSO regression and Nomogram evaluated the diagnostic value of immune-related CRGS in RPL. Functional enrichment analysis was performed on the RPL signature CRGs. And RPL samples were grouped according to the expression of 7 RPL signature CRGs through unsupervised clustering analysis. After that, we analyzed the expression level of CRGs and immune infiltration, as well as performed immune function enrichment analysis in subtypes. In addition, we also screened potential drugs that might act on CRGs to improve the pathological mechanism of RPL. RESULTS: In this study, we uncovered that DEGs and genes in key modules derived from weighted gene co-expression network analysis (WGCNA) were involved in immune regulation. And the immune infiltration landscape of RPL was significantly different from healthy controls. Furthermore, six hub genes were screened from CRGs based on Cytohubba, and their expression profilings were verified in RPL and normal mouse samples. Besides, seven CRGs closely associated with the immune regulation of RPL were identified by Spearman correlation analysis, including SLC31A1, LIAS, DLD, DLAT, DBT, ATP7B, and ATP7A, named as immune-related CRGs. Furthermore, three subgroups clustered according to these seven genes showed significant differences in immune landscape, suggesting a remarkable effect of CRGs on immune regulation. Last but not least, we analyzed the regulation network of transcription factors, miRNAs, and CRGs, and screened potential compounds for the treatment of RPL by targeting CRGs. CONCLUSIONS: The abnormal endometrial immune microenvironment in the luteal phase was associated with the pathomechanism of RPL, and cuprotosis was closely involved in the immune microenvironment in the luteal phase endometrium of RPL. Collectively, this study revealed the potential contribution of CRGs to the pathogenesis of RPL, providing a novel breakthroughs in insights into the pathogenesis, diagnosis, and treatment of RPL.

Current Perspectives and Trend of Acupuncture in Breast Cancer-Related Symptoms: A Bibliometric Study.

Purpose: This bibliometric research aims to delineate global publication trends and emerging research interests in the use of acupuncture for breast cancer (BC)-related symptoms treatment over the past three decades. Furthermore, it identifies influential institutions, potential collaborative partners, and future research trends, thereby providing guidance for relevant, novel research directions. Methods: Scientific publications related to acupuncture for BC-related symptoms were gathered from the Web of Science Core Collection (WoSCC) from 1993 to 2023. Four software applications were principally used to analyze the resulting data: the "bibliometrix" package in the R environment (version 4.2.3), VOSviewer, CiteSpace6.1.R6, and the bibliometrics website. These applications were employed to evaluate different parameters. Results: A total of 621 papers on acupuncture in BC-related symptoms treatment were analyzed. The United States, China, and South Korea contributed the most, with Memorial Sloan Kettering Cancer Center, and Columbia University leading institutions. It is interesting to mention that Mao, Jun J. and Molassiotis, A. feature among the top 10 authors and co-cited authors. JAMA is the leading journal, with an ongoing focus on acupuncture's effectiveness. Keywords show that the initial research focus was mainly on "vasomotor symptoms", but in recent years there has been a gradual shift towards "pain", "chemotherapy-induced peripheral neuropathy (CIPN)", "electroacupuncture", and "non-specific effects". Conclusion: Acupuncture has demonstrated a unique value in the process of adjuvant treatment of BC-related symptoms, and has been shown to be effective in reducing pain, eliminating fatigue, and improving quality of life. The study of the mechanisms of acupuncture and the application of electroacupuncture are possible future research priorities in this field. This study offers a deep perspective on acupuncture for BC research, highlighting key points and future trends.

Efficacy of mesenchymal stromal cells in the treatment of unexplained recurrent spontaneous abortion in mice: An analytical and systematic review of meta-analyses.

OBJECTIVES: Unexplained recurrent spontaneous abortion (URSA) remains an intractable reproductive dilemma due to the lack of understanding of the pathogenesis. This study aimed to evaluate the preclinical evidence for the mesenchymal stromal cell (MSC) treatment for URSA. METHODS: A meticulous literature search was independently performed by two authors across the Cochrane Library, EMBASE, and PubMed databases from inception to April 9, 2023. Each study incorporated was assessed using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk of bias tool. The amalgamated standardized mean difference (SMD) accompanied by 95% confidence interval (CI) were deduced through a fixed-effects or random-effects model analysis. RESULTS: A total of ten studies incorporating 140 mice were subjected to data analysis. The MSC treatment yielded a significant reduction in the abortion rate within the URSA model (OR = 0.23, 95%CI [0.17, 0.3], P<0.00001). Moreover, it elicited a positive modulatory impact on the expression profiles of several inflammatory cytokines in the decidual tissue of URSA murine models, inclusive of IL4 (SMD 1.63, 95% CI [0.39, 2.86], P = 0.01), IL10 (SMD 1.60, 95% CI [0.58, 2.61], P = 0.002), IFN-γ (SMD -1.66, 95%CI [-2.79, -0.52], P = 0.004), and TNF-α (SMD -1.98, 95% CI [-2.93, -1.04], P< 0.0001). Subgroup analyses underscored that the administration mode of intraperitoneal and uterine horn injections, and sources of bone MSCs and adipose-derived MSCs contributed positively to the expression of IL4, IL10, and decreased the expression of IFN-γ in decidual tissue of URSA (P<0.05). Conversely, the tail vein injections subgroup was observed with no statistical significance (P>0.05). CONCLUSIONS: The findings underscore the considerable potential of MSCs in URSA therapy. Nonetheless, the demand for enhanced transparency in research design and direct comparisons between various MSC sources and administration routes in URSA is paramount to engendering robust evidence that could pave the way for successful clinical translation.

Demystifying the impact of prenatal tobacco exposure on the placental immune microenvironment: Avoiding the tragedy of mending the fold after death.

Prenatal tobacco exposure (PTE) correlates significantly with a surge in adverse pregnancy outcomes, yet its pathological mechanisms remain partially unexplored. This study aims to meticulously examine the repercussions of PTE on placental immune landscapes, employing a coordinated research methodology encompassing bioinformatics, machine learning and animal studies. Concurrently, it aims to screen biomarkers and potential compounds that could sensitively indicate and mitigate placental immune disorders. In the course of this research, two gene expression omnibus (GEO) microarrays, namely GSE27272 and GSE7434, were included. Gene set enrichment analysis (GSEA) and immune enrichment investigations on differentially expressed genes (DEGs) indicated that PTE might perturb numerous innate or adaptive immune-related biological processes. A cohort of 52 immune-associated DEGs was acquired by cross-referencing the DEGs with gene sets derived from the ImmPort database. A protein-protein interaction (PPI) network was subsequently established, from which 10 hub genes were extracted using the maximal clique centrality (MCC) algorithm (JUN, NPY, SST, FLT4, FGF13, HBEGF, NR0B2, AREG, NR1I2, SEMA5B). Moreover, we substantiated the elevated affinity of tobacco reproductive toxicants, specifically nicotine and nitrosamine, with hub genes through molecular docking (JUN, FGF13 and NR1I2). This suggested that these genes could potentially serve as crucial loci for tobacco's influence on the placental immune microenvironment. To further elucidate the immune microenvironment landscape, consistent clustering analysis was conducted, yielding three subtypes, where the abundance of follicular helper T cells (p < 0.05) in subtype A, M2 macrophages (p < 0.01), neutrophils (p < 0.05) in subtype B and CD8+ T cells (p < 0.05), resting NK cells (p < 0.05), M2 macrophages (p < 0.05) in subtype C were significantly different from the control group. Additionally, three pivotal modules, designated as red, blue and green, were identified, each bearing a close association with differentially infiltrated immunocytes, as discerned by the weighted gene co-expression network analysis (WGCNA). Functional enrichment analysis was subsequently conducted on these modules. To further probe into the mechanisms by which immune-associated DEGs are implicated in intercellular communication, 20 genes serving as ligands or receptors and connected to differentially infiltrating immunocytes were isolated. Employing a variety of machine learning techniques, including one-way logistic regression, LASSO regression, random forest and artificial neural networks, we screened 11 signature genes from the intersection of immune-associated DEGs and secretory protein-encoding genes derived from the Human Protein Atlas. Notably, CCL18 and IFNA4 emerged as prospective peripheral blood markers capable of identifying PTE-induced immune disorders. These markers demonstrated impressive predictive power, as indicated by the area under the curve (AUC) of 0.713 (0.548-0.857) and 0.780 (0.618-0.914), respectively. Furthermore, we predicted 34 potential compounds, including cyclosporine, oestrogen and so on, which may engage with hub genes and attenuate immune disorders instigated by PTE. The diagnostic performance of these biomarkers, alongside the interventional effect of cyclosporine, was further corroborated in animal studies via ELISA, Western blot and immunofluorescence assays. In summary, this study identifies a disturbance in the placental immune landscape, a secondary effect of PTE, which may underlie multiple pregnancy complications. Importantly, our research contributes to the noninvasive and timely detection of PTE-induced placental immune disorders, while also offering innovative therapeutic strategies for their treatment.

Intercellular communication involving macrophages at the maternal-fetal interface may be a pivotal mechanism of URSA: a novel discovery from transcriptomic data.

Unexplained recurrent spontaneous abortion (URSA) is a severe challenge to reproductive females worldwide, and its etiology and pathogenesis have not yet been fully clarified. Abnormal intercellular communication between macrophages (Mφ) and decidual stromal cells (DSCs) or trophoblasts has been supposed to be the key to URSA. However, the exact molecular mechanisms in the crosstalk are not yet well understood. This study aimed to explore the potential molecule mechanism that may be involved in the communication between Mφ and DSC or trophoblast cells and determine their diagnostic characteristics by using the integrated research strategy of bioinformatics analysis, machine learning and experiments. First, microarrays of decidual tissue (GSE26787, GSE165004) and placenta tissue (GSE22490) in patients with URSA, as well as microarrays involving induced decidualization (GSE94644) and macrophage polarization in vitro (GSE30595) were derived from the gene expression omnibus (GEO) database. And 721 decidua-differentially expressed genes (DEGs), 613 placenta-DEGs, 510 Mφ polarization DEGs were obtained in URSA by differential expression analysis. Then, the protein-protein interaction (PPI) network was constructed, and the hub genes were identified by CytoHubba in Cytoscape software and validated by real-time PCR assay. Subsequently, immune enrichment analysis on decidua-DEGs and placenta-DEGs by ClueGO verified their regulation effects on Mφ. Besides, functional enrichment analysis was performed on Mφ polarization DEGs and the essential module genes derived from the weighted gene co-expression network analysis (WGCNA) to uncover the biological function that were related to abnormal polarization of Mφ. Furthermore, we screened out 29, 43 and 22 secreted protein-encoding genes from DSC-DEGs, placenta-DEGs and Mφ polarization DEGs, respectively. Besides, the hub secreted-protein-encoding genes were screened by CytoHubba. Moreover, we conducted functional enrichment analysis on these genes. And spearman correlation analysis between hub secreted-protein-encoding genes from donor cells and hub genes in recipient cells was performed to further understand the molecular mechanism of intercellular communication further. Moreover, signature genes with diagnostic value were screened from secreted protein-encoding genes by machine learning and validated by immunofluorescence co-localization analysis with clinical samples. Finally, three biomarkers of DSCs (FGF9, IL1R2, NID2) and three biomarkers of Mφ (CFB, NID2, CXCL11) were obtained. In conclusion, this project provides new ideas for understanding the mechanism regulatory network of intercellular communication involving macrophages at the maternal-fetal interface of URSA. Also, it provides innovative insights for the diagnosis and treatment of URSA.

Carnitine palmitoyltransferase 1A promotes mitochondrial fission by enhancing MFF succinylation in ovarian cancer.

Mitochondria are dynamic organelles that are important for cell growth and proliferation. Dysregulated mitochondrial dynamics are highly associated with the initiation and progression of various cancers, including ovarian cancer. However, the regulatory mechanism underlying mitochondrial dynamics is still not fully understood. Previously, our study showed that carnitine palmitoyltransferase 1A (CPT1A) is highly expressed in ovarian cancer cells and promotes the development of ovarian cancer. Here, we find that CPT1A regulates mitochondrial dynamics and promotes mitochondrial fission in ovarian cancer cells. Our study futher shows that CPT1A regulates mitochondrial fission and function through mitochondrial fission factor (MFF) to promote the growth and proliferation of ovarian cancer cells. Mechanistically, we show that CPT1A promotes succinylation of MFF at lysine 302 (K302), which protects against Parkin-mediated ubiquitin-proteasomal degradation of MFF. Finally, the study shows that MFF is highly expressed in ovarian cancer cells and that high MFF expression is associated with poor prognosis in patients with ovarian cancer. MFF inhibition significantly inhibits the progression of ovarian cancer in vivo. Overall, CPT1A regulates mitochondrial dynamics through MFF succinylation to promote the development of ovarian cancer. Moreover, our findings suggest that MFF is a potential therapeutic target for ovarian cancer.

Neutrophil to high-density lipoprotein cholesterol ratio as the risk mark in patients with type 2 diabetes combined with acute coronary syndrome: a cross-sectional study.

Chronic inflammation and dyslipidemia are important risk factors in developing atherosclerotic cardiovascular disease, such as coronary heart disease. Acute coronary syndrome (ACS) is one of the most dangerous syndromes in coronary heart disease. Type 2 diabetes mellitus (T2DM) is considered equal to coronary heart disease owing to the high cardiac risk induced by chronic inflammation and dyslipidemia. The neutrophil to high-density lipoprotein cholesterol ratio (NHR) is a novel and straightforward marker that reflects inflammation and lipid metabolic disorder. However, few studies have been on the role of NHR in assessing the risk of ACS in T2DM patients. Here we analyzed NHR level in ACS patients with T2DM, exploring its predictive and diagnostic values. 211 hospitalized ACS patients with T2DM were recruited as the case group, and 168 hospitalized T2DM patients as the control group (all patients collected from 6/2020 to 12/2021 in Xiangya Hospital). Biochemical test results and echocardiograms, as well as demographic information such as age, BMI, diabetes mellitus, smoking, drinking, and history of hypertension, were recorded. Frequencies, percentages, means, and standard deviations were used to describe the data. The shapiro-Wilk test was used to assess the normality of the data. Normally distributed data were compared using the independent sample T-test, and non-normally distributed data were compared using Mann-Whitney U test. Correlation analysis was performed using the Spearman rank correlation test, and receiver operating characteristic (ROC) curve analysis and multivariable logistic regression analysis were performed by SPSS version 24.0 (SPSS Inc) and GraphPad Prism 9.0 (GraphPad Software Inc). p < 0.05 was considered significant. In the study population, NHR was higher in patients with T2DM combined with ACS than in T2DM patients without ACS (p < 0.001). After adjusting for BMI, alcohol consumption, and history of hypertension, multifactorial logistic regression analysis revealed that NHR is a risk factor for T2DM patients combined with ACS (OR 1.221, p = 0.0126). Correlation analysis on all ACS patients with T2DM showed that NHR level was positively correlated with cTnI (r = 0.437, p < 0.001), CK (r = 0.258, p = 0.001), CK-Mb (r = 0.447, p < 0.001), LDH (r = 384, p < 0.001), Mb (r = 0.320, p < 0.001), LA (r = 0.168, p = 0.042) and LV levels (r = 0.283, p = 0.001). And meanwhile, NHR level was negatively correlated with EF (r = - 0.327, p < 0.001) and FS levels (r = - 0.347, p < 0.001). ROC curve analysis showed that NHR ≧ 4.32 had a sensitivity of 65.45% and a specificity of 66.19% for predicting ACS in T2DM patients [area under the curve (AUC) = 0.722, p < 0.001]. Furthermore, in all ACS patients with T2DM, the diagnostic power of NHR was stronger in ST-segment elevated ACS patients (STE-ACS) than that in non-ST-segment elevated ACS patients (NSTE-ACS) (p < 0.001). With its convenience and effective character, NHR could be a potential and new marker for predicting the presence, progression, and severity of ACS in T2DM population.

Human bone marrow-derived mesenchymal stem overexpressing microRNA-124-3p inhibit DLBCL progression by downregulating the NFATc1/cMYC pathway.

BACKGROUND: Exosomes play important roles in intercellular communication by delivering microRNAs (miRNAs) that mediate tumor initiation and development, including those in diffuse large B cell lymphoma (DLBCL). To date, however, limited studies on the inhibitory effect of exosomes derived from human bone marrow mesenchymal stem cells (hBMSCs) on DLBCL progression have been reported. Therefore, this study aimed to investigate the role of hBMSC exosomes carrying microRNA-124-3p in the development of DLBCL. METHODS: Microarray-based expression analysis was adopted to identify differentially expressed genes and regulatory miRNAs, which revealed the candidate NFATc1. Next, the binding affinity between miR-124-3p and NFATc1 was detected by luciferase activity assays. The mechanism underlying NFATc1 regulation was investigated using lentiviral transfections. Subsequently, DLBCL cells were cocultured with exosomes derived from hBMSCs transfected with a miR-124-3p mimic or control. Proliferation and apoptosis were measured in vitro. Finally, the effects of hBMSC-miR-124-3p on tumor growth were investigated in vivo. RESULTS: MiR-124-3p was expressed at low levels, while NFATc1 was highly expressed in DLBCL cells. MiR-124-3p specifically targeted and negatively regulated the expression of NFATc1 in DLBCL cells, upregulated miR-124-3p-inhibited DLBCL cell proliferation and promoted apoptosis. The miR-124-3p derived from hBMSCs inhibits tumor growth both in vivo and in vitro via downregulation of the NFATc1/cMYC pathway. CONCLUSION: Human bone marrow-derived mesenchymal stem cell overexpressing microRNA-124-3p represses the development of DLBCL through the downregulation of NFATc1.

Effects of different heat treatments on Maillard reaction products and volatile substances of camel milk.

Camel milk has unique compositional, functional and therapeutic properties compared to cow's milk and also contains many protective proteins with anti-cancer, anti-diabetic and anti-bacterial properties. In this experiment, fresh camel milk was heat-treated at different temperatures and times, and the changes in Millard reaction products were analyzed. Meanwhile, headspace-gas chromatography-ion migration spectrometry (HS-GC-IMS), electronic nose and electronic tongue were used to analyze the changes of volatile components in camel milk after different heat treatments. The results showed that the Maillard reaction was more severe with the increase of heat treatment, and the contents of furosine and 5-hydroxymethylfurfural increased significantly when the heat treatment temperature was higher than 120°C. HS-GC-IMS results showed that the contents of aldehydes and ketones increased obviously with the increase of heat treatment degree. The study clarifies the effects of different heat treatment degrees on Maillard reaction degree and flavor of camel milk, which has practical production guidance significance for the research and industrialization of liquid camel milk products.

[Standard Process for Palliative Sedation in Peking Union Medical College Hospital].

End-stage patients experience unbearable pain because of refractory symptoms.Palliative sedation is a form of palliative care which relieves patients' agony by lowering their consciousness.Standard palliative sedation can help patients die with dignity.It is distinct from euthanasia and does not alter the survival of patients.Sufficient palliative care is the premise of palliative sedation.Repeated and detailed clinical evaluation,as well as multidisciplinary involvement,is necessary for the standardized implementation of palliative sedation.Here,we proposed the standard process and specifications of palliative sedation in Peking Union Medical College Hospital.Furthermore,we reported a case of palliative sedation for an advanced cancer patient with refractory delirium and living pain to demonstrate its application in clinical practice.

[Obstacles in the Practice of Palliative Care Consultation Services in Grade A Tertiary Hospitals].

Objective To explore the obstacles in palliative care consultation services and put forward the suggestions for improving the services in grade A tertiary hospitals. Methods A semi-structured interview was conducted with 17 medical workers who had requested palliative care consultation services in Peking Union Medical College Hospital. Results The palliative care consultation services were hindered by five obstacle factors including insufficient knowledge of patients and their families about palliative care,unsound understanding of medical workers about palliative care,poor implementation of consultation opinions,limited labor of palliative care team,and poor economic benefits from palliative care.In view of such obstacles,the following suggestions were put forward,which included increasing the acceptance of palliative care by patients and their families,enriching the knowledge of medical staff on palliative care,establishing a new cooperation model between consultation team and medical staff,strengthening the institutional guarantee for the development of palliative care,and establishing and perfecting the laws and policies related to palliative care. Conclusion Although there are many difficulties in the in-hospital palliative care consultation services in grade A tertiary hospitals,the demand and expectation of medical staff for palliative care are still increasing.

[Practice of Palliative Care Consultation Proposed by the Emergency Department in Peking Union Medical College Hospital].

Objective To summarize the palliative care consultations proposed by the Emergency Department of Peking Union Medical College Hospital. Methods A retrospective study was conducted on 22 palliative care consultations in the Emergency Department of Peking Union Medical College Hospital from January 2017 to June 2020. Results A total of 18 patients (6 males and 12 females) received palliative care consultations in the Emergency Department,with the average age of (65±8) years (36-88 years).Specifically,10 and 6 patients received once and twice consultations,respectively,and 2 patients did not complete the consultation.Of the patients receiving palliative care consultations,15 had malignant tumors and 3 had non-neoplastic diseases.The reasons for palliative care consultations included communication (61.1%,11/18) and pain relief (61.1%,11/18).In terms of the place of death,8 patients died in the hospital and 6 patients in other medical institutions. Conclusion There is a clear demand for palliative care consultation in the Emergency Department of Peking Union Medical College Hospital,and the consultation can bring help to both emergency doctors and patients.

Deciphering the endometrial immune landscape of RIF during the window of implantation from cellular senescence by integrated bioinformatics analysis and machine learning.

Recurrent implantation failure (RIF) is an extremely thorny issue in in-vitro fertilization (IVF)-embryo transfer (ET). However, its intricate etiology and pathological mechanisms are still unclear. Nowadays, there has been extensive interest in cellular senescence in RIF, and its involvement in endometrial immune characteristics during the window of implantation (WOI) has captured scholars' growing concerns. Therefore, this study aims to probe into the pathological mechanism of RIF from cellular senescence and investigate the correlation between cellular senescence and endometrial immune characteristics during WOI based on bioinformatics combined with machine learning strategy, so as to elucidate the underlying pathological mechanisms of RIF and to explore novel treatment strategies for RIF. Firstly, the gene sets of GSE26787 and GSE111974 from the Gene Expression Omnibus (GEO) database were included for the weighted gene correlation network analysis (WGCNA), from which we concluded that the genes of the core module were closely related to cell fate decision and immune regulation. Subsequently, we identified 25 cellular senescence-associated differentially expressed genes (DEGs) in RIF by intersecting DEGs with cellular senescence-associated genes from the Cell Senescence (CellAge) database. Moreover, functional enrichment analysis was conducted to further reveal the specific molecular mechanisms by which these molecules regulate cellular senescence and immune pathways. Then, eight signature genes were determined by the machine learning method of support vector machine-recursive feature elimination (SVM-RFE), random forest (RF), and artificial neural network (ANN), comprising LATS1, EHF, DUSP16, ADCK5, PATZ1, DEK, MAP2K1, and ETS2, which were also validated in the testing gene set (GSE106602). Furthermore, distinct immune microenvironment abnormalities in the RIF endometrium during WOI were comprehensively explored and validated in GSE106602, including infiltrating immunocytes, immune function, and the expression profiling of human leukocyte antigen (HLA) genes and immune checkpoint genes. Moreover, the correlation between the eight signature genes with the endometrial immune landscape of RIF was also evaluated. After that, two distinct subtypes with significantly distinct immune infiltration characteristics were identified by consensus clustering analysis based on the eight signature genes. Finally, a "KEGG pathway-RIF signature genes-immune landscape" association network was constructed to intuitively uncover their connection. In conclusion, this study demonstrated that cellular senescence might play a pushing role in the pathological mechanism of RIF, which might be closely related to its impact on the immune microenvironment during the WOI phase. The exploration of the molecular mechanism of cellular senescence in RIF is expected to bring new breakthroughs for disease diagnosis and treatment strategies.

The Flavonoid Naringenin Alleviates Collagen-Induced Arthritis through Curbing the Migration and Polarization of CD4+ T Lymphocyte Driven by Regulating Mitochondrial Fission.

Rheumatoid arthritis (RA) is a progressive autoimmune disease. Due to local infiltration and damage to the joints, activated CD4+ T cells play a crucial role in the progression of RA. However, the exact regulatory mechanisms are perplexing, which makes the effective management of RA frustrating. This study aimed to investigate the effect of mitochondria fission on the polarization and migration of CD4+ T cells as well as the regulatory mechanism of NAR, so as to provide enlightenment on therapeutic targets and novel strategies for the treatment of RA. In this study, a collagen-induced arthritis (CIA) model was established, and rats were randomly given saline or naringenin (NAR, 10 mg/kg, 20 mg/kg, 50 mg/kg, i.p.) once a day, before being euthanized on the 42nd day of primary immunization. The pain-like behavior, articular index scores, account of synovial-infiltrated CD4+ T cells, and inflammatory factors were investigated in each group. In vitro, spleen CD4+ T lymphocytes were derived from each group. In addition, mitochondrial division inhibitor 1 (Mdivi-1) or NAR was added to the cell medium containing C-X-C motif chemokine ligand 12 (CXCL12) in order to induce CD4+ T lymphocytes, respectively. The polarization capacity of CD4+ T cells was evaluated through the immunofluorescence intensity of the F-actin and myosin light chain phosphorylated at Ser19 (pMLC S19), and the mitochondrial distribution was determined by co-localization analysis of the translocase of outer mitochondrial membrane 20 (TOM20, the mitochondrial marker) and intercellular adhesion molecule 1 (ICAM1, the uropod marker). The mitochondrial fission was investigated by detecting dynamin-related protein 1 (Drp1) and mitochondrial fission protein 1 (Fis1) using Western blot and immunofluorescence. This study revealed that high-dose NAR (50 mg/kg, i.p.) alleviated pain-like behavior and articular index scores, reduced the serum level of interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), and accounted for CD4+ T lymphocytes that infiltrated into the synovial membrane of the CIA group. Meanwhile, NAR (50 mg/kg, i.p.) suppressed the polarization of spleen CD4+ T lymphocytes, reduced the redistribution of mitochondria in the uropod, and inhibited the expression of Drp1 and Fis1 in the CIA model. Furthermore, the in vitro experiments confirmed that NAR reduced mitochondrial fission, which in turn inhibited the CXCL12-induced polarization and migration of CD4+ T lymphocytes. Our results demonstrated that the flavonoid NAR was a promising drug for the treatment of RA, which could effectively interfere with mitochondrial fission, thus inhibiting the polarization and migration of CD4+ T cells in the synovial membrane.

How to Screen and Prevent Metabolic Syndrome in Patients of PCOS Early: Implications From Metabolomics.

Background: Polycystic ovary syndrome (PCOS) is a complex reproductive endocrine disorder. And metabolic syndrome (MS) is an important bridge for PCOS patients to develop other diseases, such as diabetes and coronary heart disease. Our aim was to study the potential metabolic characteristics of PCOS-MS and identify sensitive biomarkers so as to provide targets for clinical screening, diagnosis, and treatment. Methods: In this study, 44 PCOS patients with MS, 34 PCOS patients without MS, and 32 healthy controls were studied. Plasma samples of subjects were tested by ultraperformance liquid chromatography (UPLC) system combined with LTQ-orbi-trap mass spectrometry. The changes of metabolic characteristics from PCOS to PCOS-MS were systematically analyzed. Correlations between differential metabolites and clinical characteristics of PCOS-MS were assessed. Differential metabolites with high correlation were further evaluated by the receiver operating characteristic (ROC) curve to identify their sensitivity as screening indicators. Results: There were significant differences in general characteristics, reproductive hormone, and metabolic parameters in the PCOS-MS group when compared with the PCOS group and healthy controls. We found 40 differential metabolites which were involved in 23 pathways when compared with the PCOS group. The metabolic network further reflected the metabolic environment, including the interaction between metabolic pathways, modules, enzymes, reactions, and metabolites. In the correlation analysis, there were 11 differential metabolites whose correlation coefficient with clinical parameters was greater than 0.4, which were expected to be taken as biomarkers for clinical diagnosis. Besides, these 11 differential metabolites were assessed by ROC, and the areas under curve (AUCs) were all greater than 0.7, with a good sensitivity. Furthermore, combinational metabolic biomarkers, such as glutamic acid + leucine + phenylalanine and carnitine C 4: 0 + carnitine C18:1 + carnitine C5:0 were expected to be sensitive combinational biomarkers in clinical practice. Conclusion: Our study provides a new insight to understand the pathogenesis mechanism, and the discriminating metabolites may help screen high-risk of MS in patients with PCOS and provide sensitive biomarkers for clinical diagnosis.

Bufalin inhibits human diffuse large B-cell lymphoma tumorigenesis by inducing cell death through the Ca2+/NFATC1/cMYC pathway.

The 5-year survival rate of diffuse large B-cell lymphoma (DLBCL) can reach 60%. However, nearly half of patients undergo relapse/refractory issues with a survival period of less than 2 years. New therapeutic approaches are therefore needed to improve chemotherapy efficacy and patient survival. Bufalin (BF), isolated from the traditional Chinese medicine Chansu, has been reported to play an anticancer role in multiple cancer cell types. However, there are few reports of the effects of BF on the growth of DLBCL. In the present study, we demonstrated that BF exerts antitumor activity in DLBCL cells, both in vitro and in vivo. Treatment of DLBCL cells with BF resulted in increased proliferation and apoptosis in a dose- and time-dependent manner. Daily intraperitoneal injection of 1.5 mg/kg BF significantly delayed DLBCL xenograft growth in NOD/SCID mice without affecting body weight. Bioinformatics analysis showed that BF may regulate NFATC1 protein and affect expression of its downstream gene, cMYC. Our results suggest that BF can attenuate NFATC1 translocation by reducing the intracellular calcium concentration; BF may also have a low synergistic effect with cyclosporin A. In conclusion, we demonstrated that BF exerts antitumor activity that is mediated at least in part by the Ca2+/NFATC1/cMYC pathway. Our findings suggest that BF can be effectively applied as a novel potential therapeutic agent for DLBCL.

Bufalin: A Systematic Review of Research Hotspots and Antitumor Mechanisms by Text Mining and Bioinformatics.

Bufalin is an anticancer drug extract from traditional Chinese medicine. Several articles about bufalin have been published. However, the literature on bufalin has not yet been systematically studied. This study aimed to identify the study status and knowledge structures of bufalin and to summarize the antitumor mechanism. Data were retrieved and downloaded from the PubMed database. The softwares of BICOMB, gCLUTO, Ucinet 6.0, and NetDraw2.084 were used to analyze these publications. The bufalin related genes were recognized and tagged by ABNER software. Then these BF-related genes were performed by Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis, and protein-protein interaction (PPI) network analysis. A total of 474 papers met the search criteria from 2000 to 2019. By biclustering clustering analysis, the 50 high-frequency main MeSH terms/subheadings were classified into 5 clusters. The clusters of drug therapy and the mechanism of bufalin were hotspot topics. A total of 50 genes were identified as BF-related genes. PPI network analysis showed that inducing apoptosis was the main effect of bufalin, and apoptosis-related gene Caspase 3 was the most reported by people. Bufalin could inhibit the proliferation, invasion, and metastasis of cancer cells through multiple signaling pathways, such as PI3K/AKT, Hedgehog, MAPK/JNK, Wnt/[Formula: see text]-catenin, TGF-[Formula: see text]/Smad, Integrin signaling pathway, and NF-KB signaling pathway via KEGG analysis. Through the quantitative analysis of bufalin literature, we revealed the research status and hot spots in this field and provided some guidance for further research.

Comparative efficacy and safety of mycophenolate mofetil and cyclophosphamide in the induction treatment of lupus nephritis: A systematic review and meta-analysis.

BACKGROUND: Lupus nephritis (LN) remains a predominant cause of morbidity and mortality in SLE. Here we performed a meta-analysis to evaluate the efficacy and safety of the induction treatment with mycophenolate mofetil (MMF) and cyclophosphamide (CYC) for LN. METHODS: Relevant literature was searched by computer from the establishment of the database to November 2019. A meta-analysis was conducted to analysis the efficacy and safety between mycophenolate mofetil and cyclophosphamide as induction therapy in LN patients. The primary end-point was response to urine protein, serum creatinine (Scr) and serum complement C3, and the secondary end-points were complete remission and adverse reactions. RESULTS: Eighteen articles were selected for the final meta-analysis, involving 1989 patients with LN, of which the renal biopsy result could be classified into class III-V according to the standards of WHO/ISN. The results revealed that MMF was superior to CYC in increasing the level of serum complement C3 [SMD = 0.475, 95%CI (0.230-0.719)] and complete remission [RR = 1.231, 95%CI (1.055-1.437)]. Furthermore, the subgroup analysis showed that it was in Asian patients, rather than in Caucasian patients, that CYC exerted a better effect on lowering the level of urine protein (UPRO) than MMF [SMD = 0.405, 95%CI (0.081-0.730)]. Besides, when the initial UPRO level was less than 4 g/day, the effect of CYC was better than MMF [SMD = 0.303, 95%CI (0.014-0.591)]. There was no significant difference between MMF and CYC in improving Scr [SMD = 0.090, 95%CI (-0.060-0.239)]. When it came to the comparison of safety between MMF and CYC, the meta-analysis showed that MMF was superior to CYC in decreasing infection in Caucasian patients [RR = 0.727, 95%CI (0.532-0.993)], reducing the risk of leukopenia and menstrual abnormalities in Asian patients and lowering the frequency of gastrointestinal symptoms [RR = 0.639, 95%CI (0.564-0.724)], independent of race. CONCLUSIONS: MMF precedes CYC in improving serum complement C3 and complete remission regardless of race, as well as shows fewer adverse drug reactions in the induction treatment of LN belonging to type III-V. But for Asian patients or those initial UPRO levels are less than 4 g/day, CYC may be superior to MMF.

Physiological and pathological regulation of autophagy in pregnancy.

Autophagy exists widely in eukaryotic cells and is regulated by a variety of molecular mechanisms. Its physiological functions include providing energy, maintaining cell homeostasis, and promoting apoptosis of abnormal cells. At present, the regulation of autophagy in tumor, degenerative disease, and cardiovascular disease has attracted much attention. Gradually, the role of autophagy in pregnancy tends to be valued. The previous literature has shown that autophagy can influence the occurrence and maintenance of pregnancy from three aspects: embryo (affecting the process of fertilization and embryonic development and the function of trophoblast cells), maternal (decidualization), and maternal-to-fetal immune crosstalk. Undoubtedly, abnormalities in autophagy levels are associated with a variety of pregnancy complications, such as preeclampsia, fetal growth restriction, and preterm delivery which have been proven by human, animal, and in vitro experiments. The regulation of autophagy is expected to be a target for the treatment of these pregnancy complications. This article reviews the research on autophagy, especially about its physiological and pathological regulation during pregnancy.

Analysis of the susceptibility to COVID-19 in pregnancy and recommendations on potential drug screening.

To analyze the susceptibility of SARS-CoV-2 in pregnancy and the drugs that can be used to treat pregnancy with COVID-19, so as to provide evidence for drug selection in clinic. By reviewing the existing literature, this paper analyzes the susceptibility of pregnant women to virus, especially to SARS-CoV-2, from the aspects of anatomical, reproductive endocrine and immune changes during pregnancy and screens effective and fetal-safe treatments from the existing drugs. The anatomical structure of the respiratory system is changed during pregnancy, and the virus transmitted by droplets and aerosols is more easily inhaled by pregnant women and is difficult to remove. Furthermore, the prognosis is worse after infection when compared with non-pregnancy women. And changes in reproductive hormones and immune systems during pregnancy collectively make them more susceptible to certain infections. More importantly, angiotensin-converting enzyme (ACE)-2, the SARS-CoV-2 receptor, has been proven highly increased during pregnancy, which may contribute to the susceptibility to SARS-CoV-2. When it comes to treatment, specific drugs for COVID-19 have not been found at present, and taking old drugs for new use in treating COVID-19 has become an emergency method for the pandemic. Particularly, drugs that show superior maternal and fetal safety are worthy of consideration for pregnant women with COVID-19, such as chloroquine, metformin, statins, lobinavir/ritonavir, glycyrrhizic acid, and nanoparticle-mediated drug delivery (NMDD), etc. Pregnant women are susceptible to COVID-19, and special attention should be paid to the selection of drugs that are both effective for maternal diseases and friendly to the fetus. However, there are still many deficiencies in the study of drug safety during pregnancy, and broad-spectrum, effective and fetal-safe drugs for pregnant women need to be developed so as to cope with more infectious diseases in the future.