Fibrosis is a defining feature of endometriosis (EMS). Our previous single-cell RNA sequencing (scRNA-seq) revealed myofibroblasts (MFBs) as the predominant cells in ectopic endometrium (ECE), mainly derived from fibroblast-to-myofibroblast transition (FMT) driven by transforming growth factor (TGF)-β pathways. Insulin-like growth factor binding proteins (IGFBPs), known regulators of fibrosis in other diseases, remain unexplored in EMS. This study investigated the role of IGFBPs in TGF-β1-induced FMT during EMS-associated fibrosis. We found that elevated TGF-β1 and TGF-βR1 in the EMS microenvironment promoted MFB formation via Smad2/3 and ERK1/2 signaling. IGFBP1 and IGFBP2 were upregulated, whereas IGFBP6 was downregulated in ectopic endometrial stromal cells (EcESCs), and all interacted with TGF-β1. Importantly, IGFBP6 suppressed TGF-β1-induced FMT and fibrosis. This is the first study to define the role of IGFBPs in EMS fibrosis, highlighting IGFBP6 as a potential antifibrotic factor and therapeutic target.

Background:Diabetic kidney disease (DKD) is one of the primary factors leading to end-stage renal disease. Ferroptosis, as a mechanism-related form of programmed cell death, has garnered increasing attention in DKD research. This study aimed to identify and validate ferroptosis-related diagnostic biomarkers for DKD. Methods:Public DKD transcriptomic datasets were analyzed using differential expression analysis, WGCNA, and multiple machine-learning algorithms to identify key ferroptosis-related genes and construct a logistic regression diagnostic model. Candidate biomarkers were validated in Nephroseq V5 platform, a real-world clinical cohort by ELISA, a human kidney single-cell RNA-seq dataset, and an STZ-induced DKD rat model. Results:Thirty-two ferroptosis-related module-specific differentially expressed genes were identified, from which COL14A1, ACADSB, TYRO3, and ZFP36 were selected as key biomarkers. The four-gene diagnostic model showed strong discriminatory performance in the training dataset and maintained diagnostic value in three independent validation datasets. In the real-world cohort, creatinine-corrected urinary levels of the four corresponding proteins were positively correlated with urinary albumin-to-creatinine ratio and negatively correlated with estimated glomerular filtration rate, and the combined urinary predictor showed high diagnostic performance for DKD. Single-cell analysis revealed cell-type-specific expression patterns, including COL14A1 enrichment in juxtaglomerular/interstitial cells and TYRO3 enrichment in podocytes, with remodeling of TYRO3-associated intercellular communication in DKD. In DKD rat kidneys, Col14a1 and Acsl4 were upregulated, whereas Tyro3 was downregulated, supporting the disease relevance of these markers. Conclusion:This multi-omics and multi-cohort study identifies COL14A1, ACADSB, TYRO3, and ZFP36 as ferroptosis-related biomarkers associated with DKD renal injury. Their creatinine-corrected urinary protein levels may serve as a promising non-invasive biomarker panel for DKD diagnosis and risk stratification.

Objective Numerous studies indicate that immune-related genes (IRGs) are closely related to tumorigenesis and tumor progression. We aimed to establish a robust IRGs-based signature to predict risk of recurrence for patients with laryngeal squamous cell carcinoma (LSCC). Methods Gene expression profiles were acquired to select differentially expressed IRGs (DEIRGs) between tumor and adjacent normal tissues. Functional enrichment analysis was performed to explore the biological roles of DEIRGs in LSCC. Univariate Cox analyses and LASSO regression model were used to construct a IRGs-based signature with the ability to predict recurrence for LSCC patients. Results A total of 272 DEIRGs were identified, of which 20 DEIRGs were significantly associated with recurrence-free survival (RFS). Subsequently, we constructed an eleven-IRGs signature that could classify patients into high-risk or low-risk groups in TCGA-LSCC training cohort. Patients in high-risk groups suffered from shorter RFS (log-rank p = 9.69E−06). Besides, the recurrence rate of high-risk group was significantly higher than that of low-risk group (41.1% vs. 13.7%; Fisher’s exact test p < 0.001). The predictive performance was validated in an independent cohort (GSE27020, log-rank p = 1.43E-03). Person correlation analysis showed that the risk scores calculated by eleven-IRGs signature were significantly associated with filtrating immune cells. Furthermore, three immune checkpoint molecules were significantly over-expressed in the high-risk group. Conclusion Our findings for the first time constructed a robust IRGs-based signature to precisely predict risk of recurrence and further provided a deeper understanding of IRGs regulatory mechanism in LSCC pathogenesis.

Abstract Background Many previous studies have reported the association between iron overload (IO) and type 2 diabetes mellitus (T2DM). However, the underlying molecular mechanism is not clear. Methods Epidemiological data from the National Health and Nutrition Examination Survey 2017–2018 (NHANES) was used to systematically explore the association between IO and diabetes. Furthermore, transcriptome data from Gene Expression Omnibus (GEO) were analyzed using bioinformatics methods to explore the underlying functional mechanisms at the molecular level. Results Data from NHANES showed a “W” shape relationship between serum iron (frozen) and the risk of diabetes (P < 0.001) as well as a “∧” shape correlation between serum unsaturated iron binding capacity (UIBC) and the risk of diabetes (P = 0.007). Furthermore, the serum iron (frozen) was positively associated with fasting plasma glucose and HOMAB (P < 0.05), and UIBC was positively associated with fasting insulin (P < 0.05). Transcriptome data showed that two IO-related genes [Transferrin receptor (TFRC) and Solute carrier family-11 member-2 (SLC11A2)] were down-regulated in T2DM. The correlation analysis showed that expression levels of TFRC and SLC11A2 were significantly and positively correlated with genes involved in insulin secretion (P < 0.05). Protein–protein interaction network analysis showed that TFRC and SLC11A2 interacted with four key genes, including VAMP2, HIF1A, SLC2A1, and RAB11FIP2. Conclusion We found that IO status was associated with increased FPG and aggravated HOMAB, and two IO-related genes (TFRC and SLC11A2) might induce the occurrence of T2DM by influencing insulin secretion, which provides potential therapeutic targets for T2DM patients.

Background: Fibrosis, chronic inflammation and neuroangiogenesis are the consistent characteristics of endometriosis (EMS). The cellular heterogeneity of ectopic and non-ectopic endometrium by single-cell RNA-sequencing(scRNA-seq)at secretory phase without the disturbance of hormone drugs hasn’t been explored so far.Methods: In this study, we adopted scRNA-seq and immunohistochemical identification to explore the properties of ectopic endometrium (ECE), eutopic endometrium (EUE) and normal endometrium (NOE) at secretory phase without the influence of exogenous hormones.Findings(i): The ratio of myofibroblasts, pericytes, endothelial cells and macrophages in ECE overwhelms the non-ectopic tissues (EUE and NOE) and myofibroblasts were the most abundant cells in ECE. (ii) Thefibroblast-to-myofibroblast transdifferentiation (FMT)-derived myofibroblasts, expecially myofibroblasts C2, have the ECE-specific development state and maybe associated with fibrosis in ECE. (iii) Pericytes were endothelial cells-dependent differentiation and both of them were responsible for the angiogenesis of ECE. (iv) The increased inflammation score and deceased T cell exhaustion score and antigen-presenting capacity in ECE confirmed the immunodeficiency and inflammatory properties of ECE.Interpretation: These findings will facilitate to explore the specific diagnostic biomarkers and therapeutic targets for EMS.Funding Information: This study was supported by The scientific research project of Jiangsu Commission of Health(H2018017). The second phase of Maternal and Child Health Key Talent Project of Jiangsu Province (FRC201709).Declaration of Interests: The authors declare no conflict of interest.Ethics Approval Statement: All tissue samples were collected from the First Affiliated Hospital of NanjingMedical University and were approved by the patients and the Medical Ethics Committee (approval number 2020-SRFA-326).

Fibrosis, angiogenesis and chronic inflammation are the inherent characteristics of endometriosis (EMS). The cellular heterogeneity of ectopic and non-ectopic endometrium by single-cell RNA-sequencing (scRNA-seq)at secretory phase without the disturbance of hormone drugs hasn't been explored so far. In this study, scRNA-seq was adopted to explore the properties of ectopic endometrium (ECE), eutopic endometrium (EUE) and normal endometrium (NOE) at secretory phase. We found that (i) The proportion of myofibroblasts, pericytes, endothelial cells and macrophages in ECE overwhelms that of non-ectopic tissues (EUE and NOE), and Myofibro.C2 was the predominant myofibroblast sub-cluster in ECE. (ii) Myofibroblasts were mainly fibroblast-to-myofibroblast transdifferentiation (FMT) and pericytes were endothelial cell-dependent differentiation in ECE. (iii) Both myofibroblasts and pericytes had a low differentiation potential. (iv) The increased inflammation score, deceased NK cells, T cell exhaustion score and antigen-presenting capacity in ECE confirmed the inflammatory properties and immunodeficiency of ECE. These findings suggested that myofibroblasts, pericytes and macrophages may be the potential targets for anti-fibrotic, anti-angiogenic and anti-inflammatory therapy of EMS.

间皮囊肿是来源于间皮细胞的一种良性肿瘤性病变,主要累及盆腹腔腹膜,以肠系膜及大网膜多见,较少发生于子宫.报告南京医科大学第一附属医院收治的1例子宫间皮囊肿患者误诊为子宫肌瘤囊性变的诊治经过.该患者术前无典型临床表现,主要依据影像学特点诊断为子宫肌瘤囊性变并进行全子宫+双侧输卵管切除术,术后病理确诊为子宫间皮囊肿.通过回顾分析该患者的诊治经过并结合文献复习,探讨子宫间皮囊肿的鉴别诊断及治疗方式,以期提高妇科医生对该疾病的认识,避免误诊和漏诊.

Papillary thyroid carcinoma (PTC) is the most common thyroid cancer with a rapidly increasing incidence globally. Bioinformatics analyses suggested that SHCBP1 (SHC SH2 Domain-Binding Protein 1) was significantly up-regulated in PTC tumor tissues, which was further confirmed by immunohistochemical staining and qPCR analyses in Xuzhou cohort. Moreover, the results indicated that the mRNA level of SHCBP1 was negatively associated with patients’ disease-free survival rate, and further analysis reveals that patients with high SHCBP1 expression tend to have more lymph node metastasis. Afterward, MTT, colony formation, cell-cycle assay, FACS apoptosis assay, invasion, migration, as well as scratch assay were performed to study the phenotypes change of PTC cells after knocking down SHCBP1. The in vivo subcutaneous tumor model was developed to study the proliferation ability of PTC cells after SHCBP1 knockdown. We show that knock down of SHCBP1 significantly inhibits PTC cell proliferation, cell cycle, invasion and migration in vivo and in vitro . Western blot and qRT-PCR showed that knockdown of SHCBP1 could significantly reduce MYC, KLF4, CD44, ITGA6, ITGB1, ITGB5, and COL4A2 expression at both RNA and protein levels, which indicated that SHCBP1 might be involved in PTC carcinogenesis and progression through targeting formation of integrin and collagen and cell stemness pathways, and can be a potential diagnosis biomarker and therapeutic target for PTC.

Endometriosis (EMS) is a disease that shows immune dysfunction and chronic inflammation characteristics, suggesting a role of complement system in its pathophysiology. To find out the hub genes and pathways involved in the pathogenesis of EMs, three raw microarray datasets were recruited from the Gene Expression Omnibus database (GEO). Then, a series of bioinformatics technologies including gene ontology (GO), Hallmark pathway enrichment, protein–protein interaction (PPI) network and gene co-expression correlation analysis were performed to identify hub genes. The hub genes were further verified by the Real-time quantitative polymerase chain reaction (RT-PCR) and Western Blot (WB). We identified 129 differentially expressed genes (DEGs) in EMs, of which 78 were up-regulated and 51 were down-regulated. Through GO functional enrichment analysis, we found that the DEGs are mainly enriched in cell adhesion, extracellular matrix remodeling, chemokine regulation, angiogenesis regulation, epithelial cell proliferation, et al. In Hallmark pathway enrichment analysis, coagulation pathway showed great significance and the terms in which included the central complement factors. Moreover, the genes were dominating in PPI network. Combined co-expression analysis with experimental verification, we found that the up-regulated expression of complement (C1S, C1QA, C1R, and C3) was positively related to tissue factor (TF) in EMs. In this study, we discovered the over expression complement and the positive correlation between complement and TF in EMs, which suggested that interaction of complement and coagulation system may play a role within the pathophysiology of EMS.

Accumulating evidence has demonstrated that circular RNAs (circRNAs) play vital roles in cancer progression. However, the underlying molecular mechanisms of circRNAs remain poorly elucidated in gastric cancer (GC). The main purpose of present study is to explore the underlying regulatory mechanism by constructing a circRNA-associated competitive endogenous RNA (ceRNA) network and further establish a robust prognostic signature for patients with GC. Based on expression data of circRNA, microRNA, and mRNA derived from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases, a circRNA-associated ceRNA network, containing 15 cirRNAs, 9 microRNAs, and 35 mRNAs, was constructed using the Starbase database. Functional enrichment analysis showed that the ceRNA network might be involved in many cancer-related pathways, such as regulation of transcription from RNA polymerase II promoter, mesodermal cell differentiation, and focal adhesion. A protein-protein interaction network was constructed based on genes within the circRNA-associated ceRNA network. We found that six of ten hub genes within the PPI network were significantly associated with overall survival (OS). Thus, using the LASSO method, we constructed a three-gene prognostic signature based on TCGA-GC cohort, which could classify GC patients into low-risk and high-risk groups with significant difference in OS (HR=1.9, 95%CI=1.14‐3.2, and log-rank p=0.001). The prognostic performance of the three-gene signature was verified in GSE15459 (HR=1.9, 95%CI=1.27‐3.0, and log−rank p=2.2E−05) and GSE84437 (HR=1.5, 95%CI=1.17‐2.0, and log−rank p=6.3E−04). Multivariate Cox analysis further revealed that the three-gene prognostic signature could serve as an independent risk factor for OS. Taken together, our findings contribute to a better understanding of the underlying mechanisms of circRNAs in GC progression. Furthermore, a robust prognostic signature is meaningful to facilitate individualized treatment for patients with GC.

Background High-intensity focused ultrasound (HIFU) is a promising and non-invasive therapy for symptomatic uterine fibroids. Currently, the main image-guided methods for HIFU include magnetic resonance-guided (MR-HIFU) and ultrasound-guided (US-HIFU). However, there are few comparative studies on the therapeutic efficacy and safety of MR-HIFU and US-HIFU in treating symptomatic uterine fibroids with a volume <300 cm3. Objective We performed this meta-analysis to evaluate the efficacy and safety of MR-HIFU and US-HIFU in treating symptomatic uterine fibroids with a volume <300 cm3. Methods We searched relevant literature in PubMed, EMBASE, Cochrane Library CNKI from inception until 2021. The mean value, the proportion, and their 95% confidence intervals (CIs) were measured by random-effects models. Publication bias was assessed using funnel plots. Results 48 studies met our inclusion criteria—28 describing MR-HIFU and 20 describing US-HIFU. The mean non-perfused volume rate (NPVR) was 81.07% in the US-HIFU group and 58.92% in the MR-HIFU group, respectively. The mean volume reduction rates at month-3, month-6, and month-12 were 42.42, 58.72, and 65.55% in the US-HIFU group, while 34.79, 37.39, and 36.44% in the MR-HIFU group. The incidence of post-operative abdominal pain and abnormal vaginal discharge in the US-HIFU group was lower than that of MRI-HIFU. However, post-operative skin burn and sciatic nerve pain were more common in the US-HIFU group compared with MRI-HIFU. The one-year reintervention rate after MR-HIFU was 13.4%, which was higher than 5.2% in the US-HIFU group. Conclusion US-HIFU may show better efficiency and safety than MR-HIFU in treating symptomatic fibroids with a volume <300 cm3.

Acute respiratory distress syndrome (ARDS) is difficult to treat and has a high mortality rate. Mesenchymal stem cells (MSCs) have an important therapeutic effect in ARDS. While the mechanism of MSC migration to the lungs remains unclear, the role of MSCs is of great clinical significance. To this end, we constructed vimentin knockout mice, extracted bone MSCs from the mice, and used them for the treatment of LPS-induced ARDS. H&E staining and Masson staining of mouse lung tissue allowed us to assess the degree of damage and fibrosis of mouse lung tissue. By measuring serum TNF-α, TGF-β, and INF-γ, we were able to monitor the release of inflammatory factors. Finally, through immunoprecipitation and gene knockout experiments, we identified upstream molecules that regulate vimentin and elucidated the mechanism that mediates MSC migration. As a result, we found that MSCs from wild-type mice can significantly alleviate ARDS and reduce lung inflammation, while vimentin gene knockout reduced the therapeutic effect of MSCs in ARDS. Cytological experiments showed that vimentin gene knockout can significantly inhibit the migration of MSCs and showed that it changes the proliferation and differentiation status of MSCs. Further experiments found that vimentin's regulation of MSC migration is mainly mediated by Rab7a. Rab7a knockout blocked the migration of MSCs and weakened the therapeutic effect of MSCs in ARDS. In conclusion, we have shown that the Vimentin-Rab7a pathway mediates migration of MSCs and leads to therapeutic effects in ARDS.

AbstractAims/IntroductionType 2 diabetes mellitus is a chronic metabolic disorder characterized by islet β‐cell dysfunction, which might result from the activation of islet stellate cells (ISCs). Our recent study showed that a specific population of ISCs is prone to be activated in type 2 diabetes mellitus accompanied by reduced secretion of insulin. The wingless‐type MMTV integration site family member 5a (Wnt5a)/frizzled‐5 signaling pathway might play an important role in this process. The present study aimed to explore the effects of Wnt5a on the activation of ISCs isolated from db/db mice.Materials and MethodsISCs were isolated from db/db mice and matched db/m mice. Immunohistochemistry and western blotting analysis were applied for the determination of Wnt5a expression. Exogenous Wnt5a and lentivirus containing the target gene Wnt5a short hairpin ribonucleic acid were used as a molecular intervention. The experiment of transwell and wound healing was used to evaluate the migration of the isolated ISCs.ResultsOur data showed that the expression of Wnt5a and frizzled‐5 was decreased in the ISCs isolated from db/db mice compared with db/m mice. Both the exogenous Wnt5a and the overexpression of Wnt5a could inhibit the outgrowth rate of ISCs from islets, and its viability, migration and α smooth muscle actin expression. These changes were associated with the inactivation of the Smad2/3 signaling pathway in a frizzled‐5‐dependent manner.ConclusionsOur observations revealed a potential role of Wnt5a in preventing ISC activation. The maintenance of quiescent ISCs might be a desirable outcome of therapeutic strategies for diabetes mellitus.

Background. Type 2 diabetes mellitus is a serious public health problem worldwide. Accumulating evidence has shown that β-cell dysfunction is an important mechanism underlying diabetes mellitus. The changes in the physiological state of islet stellate cells (ISCs) and the effects of these cells on β cell function play an important role in the development of diabetes. This study aimed at elucidating the mechanism by which ISCs regulate insulin secretion from Min6 cells via the Wnt5a protein. Methods. Glucose-stimulated insulin secretion (GSIS) from Min6 cells was examined by estimating the insulin levels in response to high glucose challenge after culture with ISC supernatant or exogenous Wnt5a. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) analyses were used to observe changes in the β-catenin, receptor tyrosine kinase-like orphan receptor 2 (Ror2), Ca (2+)/calmodulin (CaM)-dependent protein kinase II (CamKII), forkhead box O1 (FoxO1), pancreatic and duodenal homeobox 1 (PDX1), glucose transporter 2 (Glut2), insulin, and Cask mRNA and protein levels in the Wnt and insulin secretory pathways. Flow cytometry was used to confirm the intracellular Ca2+ concentration in Min6 cells. Results. We observed a significant increase in insulin secretion from Min6 cells cocultured in vitro with supernatant from db/m mouse ISCs compared to that from Min6 cells cocultured with supernatant from db/db mouse ISCs; The intracellular Ca2+ concentration in Min6 cells increased in cultured in vitro with supernatant from db/m mouse ISCs and exogenous Wnt5a compared to that from control Min6 cells. Culture of Min6 cells with exogenous Wnt5a caused a significant increase in pCamKII, pFoxO1, PDX-1, and Glut2 levels compared to those in Min6 cells cultured alone; this treatment further decreased Ror2 and Cask expression but did not affect β-catenin expression. Conclusion. ISCs regulate insulin secretion from Min6 cells through the Wnt5a protein-induced Wnt-calcium and FoxO1-PDX1-GLUT2-insulin signalling cascades.

Endometrial polyps (EPs) are a frequently encountered gynecologic disease with abnormal uterine bleeding and infertility being the two common presenting problems, and hysteroscopic polypectomy is an effective method to remove them. The postoperative polyp recurrence might result in reappearance of abnormal uterine bleeding or infertility, whereas factors influencing the postoperative recurrence potential have limited data. Endometrial polyp recurrence remains a concern with recurrence rates of 2.5% to 43.6%. As such, it is critical to identify the risk factors and the preventive measures for endometrial recurrence, especially in reproductive-age women desiring future conception, to aid in clinical counselling and decision making. The recurrence of EPs is related to estrogen stimulation and endometrial hyperplasia. The progesterone-containing drugs are currently the most commonly used method to prevent the recurrence of EPs. In this article, authors aim to discuss the high-risk factors of EPs recurrence and the preventive measures for EPs recurrence. The preventive measures will focus on the combined oral contraceptives (COCs) and the levonorgestrel-releasing intrauterine system (LNG-IUS).

Type 2 diabetes mellitus (T2DM) is sustained by insulin resistance (IR) and reduced β-cell mass, which is largely due to insulin secretory dysfunction. Wnt5a protein is essential to islet formation and β-cell migration in the development of pancreas in vertebrates. Levels of the Wnt5a protein antagonist plasma secreted frizzled-related protein 5 (Sfrp5) were elevated in patients with T2DM. However, the association between Wnt5a, T2DM patients and diabetic kidney disease (DKD) is unknown. We aim to investigate the circulating Wnt5a levels in in different clinical stages of T2DM and evaluate its correlation of duration of diabetes mellitus chronic complication. A total of 329 participants (187 males, 142 females; age range 40 to 80 years) were enrolled in this study. Serum Wnt5a levels were measured by an enzyme-linked immunosorbent assay (ELISA). The demographic and clinical parameters evaluated in subjects with new onset T2DM, onset T2DM after treatment and DKD at different clinical phases. Wnt5a was significantly down-regulated in newly diagnosed T2DM patients and gradually increased after 3 months of treatment. Interesting, serum wnt5a was gradually increased in patients with long-term diabetes and kidney disease compared to patients with T2DM and onset DKD. We speculated that the Wnt5a protein might regulate islet function and be involved in the onset of diabetes as a protective factor. It may be one of the inflammatory factors adversely involved in the progression of diabetic nephropathy.

Bone marrow mesenchymal stem cells (BMSCs) have the potential to transdifferentiate into cardiomyocyte-like cells (CLCs) if an appropriate cardiac environment is provided. Insulin-like growth factor-1 (IGF-1) plays an important role in the cell migration, survival and differentiation of BMSCs. However, the effect of IGF-1 on the cellular differentiation remains unclear. In the present study, BMSCs were isolated from rat femurs and tibias and the cells were purified at passage 6 (P6). IGF-1 and IGF-1 receptor (IGF-1R) kinase inhibitor I-OMe AG538 were added to detect if IGF-1 could induce BMSCs to transdifferentiate into CLCs and if I-OMe AG538 could inhibit IGF-1-mediated receptor activation and downstream signaling. Immunostaining demonstrated that all P6 BMSCs express CD29 and CD44 but not CD45. BMSCs induced by 15 ng/ml IGF-1 revealed positivity for cardiac troponin-T and cardiac troponin-I. The optimal induction time was 14 days but the expression of these proteins were incompletely inhibited by 300 nmol/l I-OMe AG538 and completely inhibited by 10 mu mol/l I-OMe AG538. Western blotting showed that the level of IGF-1R autophosphorylation and the expression of cTnT and cTnI were higher when BMSCs were induced for 14 days. I-OMe AG538 selectively inhibited IGF-1-mediated growth and signal transduction and the inhibitory effect of I-OMe AG538 were not reverted in the presence of exogenous IGF-1. In addition, when a time course analysis of the effects of I-OMe AG538 on mitogen-activated protein kinase kinase and phosphatidylinositol 3-kinase signaling were done, we observed a transient inhibitory effect on Erk1/2 and Akt phosphorylation, in keeping with the inhibitory effects on cell growth. Taken together, these data indicate that I-OMe AG538 could inhibit IGF-1-induced CLCs in BMSCs and this effect is time-and concentration-dependent.

The study was conducted to examine the effects of ICI 118,551 on the systolic function of cardiac muscle cells of rats in heart failure and determine the molecular mechanism of selective β2-adrenergic receptor (β2-AR) antagonist on these cells. The chronic heart failure model for rats was prepared through abdominal aortic constriction and separate cardiac muscle cells using the collagenase digestion method. The rats were then divided into Sham, HF and HF+ICI 50 nM goups and cultivated for 48 h. β2-AR, Gi/Gs and sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) protein expression levels in the cardiac muscle cells were evaluated by western blotting and changes in the systolic function of cardiac muscle cells based on the boundary detection system of contraction dynamics for individual cells was measured. The results showed that compared with the Sham group, the survival rate, percentage of basic contraction and maximum contraction amplitude percentage of cardiac muscle cells with heart failure decreased, Gi protein expression increased while Gs and SERCA2a protein expression decreased. Compared with the HF group, the maximum contraction amplitude percentage of cardiac muscle cells in group HF+ICI 50 nM decreased, the Gi protein expression level increased while the SERCA2a protein expression level decreased. Following the stimulation of Ca2+ and ISO, the maximum contraction amplitude percentage of cardiac muscle cells in the HF+ICI 50 nM group was lower than that in group HF. This indicated that ICI 118,551 has negative inotropic effects on cardiac muscle cells with heart failure, which may be related to Gi protein. Systolic function of cardiac muscle cells with heart failure can therefore be reduced by increasing Gi protein expression and lowering SERCA2a protein expression.

Researches regarding mitogen-inducible gene 6 (Mig-6) have confirmed its role as a tumor suppressor and progesterone resistance factor in endometrium. In this study, after confirming the downregulation of Mig-6 protein in endometrial carcinoma (EC) tissues, the expression of Mig-6 was upregulated in Ishikawa cells by pCMV6-Mig-6 plasmid. We observed the increased apoptosis, decreased proliferation and invasion potential of Ishikawa cells after upregulation of Mig-6. The proapoptosis ability of P4 significantly enhanced by 39.36%, the antiproliferation ability increased by 37.90% and the anti-invasion ability increased by 48.89%, suggesting the antiprogesterone resistance potential of Mig-6 in endometrium. In addition, the results suggested that Mig-6 may induce Ishikawa cell apoptosis through the mitochondrial pathway, inhibit cell proliferation via the extracellular signal-regulated kinase pathway and the anti-invasion potential may associate with matrix metalloproteinase (MMP)-2 and MMP-9 downexpression. Therefore, upregulation of Mig-6 may add a new strategy to suppress endometrial tumorigenesis and attenuate the progesterone resistance during P4 treatment.