Heterogeneity in extracellular matrix and immune microenvironment of anterior vaginal wall revealed by single-cell sequencing in women with stress urinary incontinence.

Stress urinary incontinence (SUI), characterized by involuntary urine leakage during increased abdominal pressure, remains poorly understood regarding its pathophysiology and treatment. In this study, we utilized single-cell sequencing to analyze the transcriptomic profiles of different cell types in anterior vaginal wall of SUI patients, aiming to explore the heterogeneity of the extracellular matrix (ECM) and immune microenvironment in SUI pathogenesis. Our results identified eleven cell types, including connective tissue cells, immune cells, and glial cells. Specifically, fibroblasts, smooth muscle cells, epithelial cells and T cells displayed transcriptional characteristics highly relevant to SUI pathogenesis. We observed that most cell types participate in ECM metabolism and immune-inflammatory responses, indicating a synergistic role of multiple vaginal cell types in SUI. Furthermore, altered intercellular communication, particularly between fibroblasts and T cells, was noted in SUI. This study provides novel single-cell insights into SUI and identifies potential biomarkers and therapeutic targets for future research.

Identification ATP5F1D as a Biomarker Linked to Diagnosis, Prognosis, and Immune Infiltration in Endometrial Cancer Based on Data-Independent Acquisition (DIA) Analysis.

In developed countries, endometrial cancer (EC) is the most prevalent gynecological cancer. ATP5F1D is a subunit of ATP synthase, as well as an important component of the mitochondrial electron transport chain (ETC). ETC plays a compelling role in carcinogenesis. To date, little is known about the role of ATP5F1D in EC. We undertook data-independent acquisition mass spectrometry (DIA-MS) of 20 EC patients, comprising 10 high-grade and 10 low-grade cancer tissues. Biological functions of differentially expressed genes (DEGs) were analyzed by GO and KEGG. The expression level, clinicopathological features, diagnostic potency, prognostic value, RNA modifications, immune characteristics, and therapy response of ATP5F1D were investigated. In total, 77 DEGs were acquired by DIA analysis, which were closely related to regulating immune response and metabolic pathways. Among the five genes (NDUFB8, SLC26A2, RAF1, ATP5F1D, and GSTM5) involving in reactive oxygen species pathway, ATP5F1D showed the most significant differential expression (2.903-fold change). We found ATP5F1D had a high diagnostic value and was associated with a favorable prognosis in EC patients. After analyzing the RNA modifications of ATP5F1D, revealing a negative regulation between them. Additionally, ATP5F1D was closely related to tumor immune infiltration. Our results suggested T-cell dysfunction and TAM-M2 polarization might be the important mechanisms of ATP5F1D to facilitate tumor immune escape. Noticeably, EC patients with ATP5F1D-high expression had better immune treatment responses and were more sensitive to chemotherapy drugs. ATP5F1D can be used as a biomarker for diagnosis, prognosis, and immune infiltration of EC, and offers a crucial reference for personalized treatment of EC patients.

Data-independent acquisition for proteomic applications in early-stage endometrial cancer progression.

AIM: Most endometrial cancer (EC) patients are diagnosed at an early-stage (FIGO stage I or II), with a favorable prognosis. However, some high-grade, early-stage EC patients have unexpected recurrences and undesirable results, the molecular alterations that underlie these tumors are far from being fully understood. Our goal was to use proteome analysis to examine dysregulated pathways in this specific subgroup of EC. METHODS: We used data-independent acquisition (DIA) quantitative proteomics to analyze cancer and matched paracancerous tissues from 20 EC patients (10 high-grade and 10 low-grade). Immunohistochemistry (IHC) analysis was used to validate protein expression of six hub genes. RESULTS: In total, 7107 proteins were quantified, while 225 downregulated and 366 upregulated proteins in high-grade cancer tissues, 130 downregulated and 413 upregulated proteins in high-grade paracancerous tissues. The pathway associated with oxidative phosphorylation (OXPHOS) was upregulated and have similar expression patterns in high-grade EC tissues and matched paracancerous tissues. OXPHOS-related protein, ATP5F1D showed the best classification and diagnostic ability in distinguishing high-grade from low-grade EC. In both cancer and paracancerous tissues, double-label immunofluorescence demonstrated ITGA4 and COL4A1 co-localized at the basal membrane. CONCLUSIONS: Our present works elucidate that metabolism reprogramming is associated with high-grade, early-stage EC, particularly OXPHOS is upregulated. Noticeably, the paracancerous tissues have undergone molecular changes similar to cancer tissues, maybe they have signal exchange via secreted proteins (ITGA4 and COL4A1). The upregulation of OXPHOS-related proteins may be the potential biomarker for EC diagnosis, and targeting OXPHOS metabolism might be an effective treatment for high-grade, early-stage EC.

Potential mechanisms and therapeutic strategies for LPS-associated female fertility decline.

As a major component of the outer membrane of Gram-negative bacteria, lipopolysaccharide (LPS) can be recognized by toll-like receptors (TLRs) and induce inflammation through MyD88 or the TIR domain-containing adapter-inducing interferon-ß (TRIF) pathway. Previous studies have found that LPS-associated inflammatory/immune challenges were associated with ovarian dysfunction and reduced female fertility. However, the etiology and pathogenesis of female fertility decline associated with LPS are currently complex and multifaceted. In this review, PubMed was used to search for references on LPS and fertility decline so as to elucidate the potential mechanisms of LPS-associated female fertility decline and summarize therapeutic strategies that may improve LPS-associated fertility decline.

Inhibition of squalene epoxidase linking with PI3K/AKT signaling pathway suppresses endometrial cancer.

Endometrial cancer (EC) is a common malignant tumor that lacks any therapeutic target and, in many cases, recurrence is the leading ca use of morbidity and mortality in women. Widely known EC has a strongly positive correlation with abnormal lipid metabolism. Squalene epoxidase (SQLE), a crucial enzyme in the cholesterol synthesis pathway regulating lipid metabolic processes has been found to be associated with various cancers in recent years. Here, we focused on studying the role of SQLE in EC. Our study revealed that SQLE expression level was upregulated significantly in EC tissues. In vitro experiments showed that SQLE overexpression significantly promoted the proliferation, and inhibited cell apoptosis of EC cells, whereas SQLE knockdown or use of terbinafine showed the opposite results. Furthermore, we found out that the promotional effect of SQLE on the proliferation of EC cells might be achieved by activating the PI3K/AKT pathway. In vivo, studies confirmed that the knockdown of SQLE or terbinafine can observably inhibit tumor growth in nude mice. These results indicate that SQLE may promote the progression of EC by activating the PI3K/AKT pathway. Moreover, SQLE is a potential target for EC treatment and its inhibitor, terbinafine, has the potential to become a targeted drug for EC treatment.

Tailoring Spin State of Perovskite Oxides by Fluorine Atom Doping for Efficient Oxygen Electrocatalysis.

Promoting the initially deficient but economical catalysts to high-performing competitors is important for developing superior catalysts. Unlike traditional nano-morphology construction methods, this work focuses on intrinsic catalytic activity enhancement via heteroatom doping strategies to induce lattice distortion and optimize spin-dependent orbital interaction to alter charge transfer between catalysts and reactants. Experimentally, a series of different concentrations of fluorine-doped lanthanum cobaltate (Fx -LaCoO3 ) exhibiting excellent electrocatalytic activity is synthesized, including a low overpotential of 390 mV at j = 10 mA cm-2 for OER and a large half-wave potential of 0.68 V for ORR. Meanwhile, the assembled rechargeable Zn-air batteries deliver an excellent performance with a large specific capacity of 811 mAh/gZn under 10 mA cm-2 and stability of charge/recharge (120 h). Theoretically, taking advantage of density functional theory calculations, it is found that the prominent OER/ORR performance arises from the spin state transition of Co3+ (Low spin state (LS, t2g 6 eg 0 ) → Intermediate spin state (IS, t2g 5 eg 1 ) and the mediated d-band center upshift by F atom incorporation. This work establishes a novel avenue for designing superior electrocatalysts in perovskite-based oxides by regulating spin states.

A nomogram-based overall survival stratification to identify uterine sarcoma patients without distant metastases who may benefit from adjuvant radiotherapy.

OBJECTIVE: Adjuvant radiotherapy has been commonly performed in uterine sarcoma patients, but its role in overall survival (OS) remains controversial. Therefore, our study aimed to build a nomogram-based prognostic stratification to identify uterine sarcoma patients who might benefit from adjuvant radiotherapy. METHODS: Uterine sarcoma patients without distant metastases between 2004 and 2015 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. The LASSO Cox regression was performed to identify essential prognostic predictors and a nomogram was built to predict the 1-, 3-, and 5-year OS. Receiver operating characteristic (ROC), calibration curves, and decision curve analysis (DCA) were used to validate the nomogram. Finally, prognostic stratification was performed by decision tree analysis based on the total points of the nomogram. RESULTS: 2871 patients with uterine sarcoma were included. Preliminary analysis suggested that adjuvant radiotherapy failed to provide an OS benefit for the total population without our nomogram. The built nomogram showed good discrimination and calibration abilities to predict the OS in uterine sarcoma patients and the patients were stratified into three risk groups based on the nomogram. For patients in the high-risk group, adjuvant radiotherapy significantly improved the 5-year OS and median survival time by 26.4% and 17 months, respectively (P < 0.001); while radiotherapy failed to improve the survival outcomes of patients in the low- and intermediate-risk groups. CONCLUSIONS: The nomogram-based prognostic stratification provides preliminary characterization of uterine sarcoma patients who may benefit from radiotherapy. The newly defined high-risk patients may gain significant OS benefit from adjuvant radiotherapy.

Correlation between malignant peritoneal cytology and survival in patients with uterine leiomyosarcoma and endometrial stromal sarcoma.

OBJECTIVE: This study aimed to examine the correlation between malignant peritoneal cytology and overall survival among patients with uterine leiomyosarcoma and endometrial stromal sarcoma. METHODS: Patients with uterine leiomyosarcoma and endometrial stromal sarcoma between January 2010 and December 2016 were identified from the Surveillance, Epidemiology, and End Results database. The multiple imputation method was used to address missing values. Propensity score matching was conducted to balance baseline data between the malignant and negative peritoneal cytology groups. The prognostic significance of malignant peritoneal cytology was evaluated using Cox regression, random survival forest, and subgroup analyses. RESULTS: Among 733 eligible patients, 8% (59/733) had malignant peritoneal cytology, increasing to 20% (42/209) in advanced cases. Before and after propensity score matching, patients with malignant peritoneal cytology had significantly lower 5-year overall survival rates and shorter median survival time than patients with negative peritoneal cytology. Multivariate Cox regression revealed that malignant peritoneal cytology (hazard ratio 2.03, 95% confidence interval 1.29 to 3.20, p=0.002) was an independent prognostic factor for uterine leiomyosarcoma and endometrial stromal sarcoma. Random survival forest further indicated that, among the factors analyzed, peritoneal cytology status was second only to the International Federation of Gynecology and Obstetrics (FIGO) stage in terms of prognostic prediction. Finally, subgroup analyses substantiated the correlation between malignant peritoneal cytology and unfavorable overall survival in most subgroups. CONCLUSIONS: Malignant peritoneal cytology status was an important prognostic factor complementing FIGO stage and was associated with a reduction in overall survival. Peritoneal cytology evaluation during hysterectomy may be recommended for prognosis estimation for uterine leiomyosarcoma and endometrial stromal sarcoma.

SIK2: A critical glucolipid metabolic reprogramming regulator and potential target in ovarian cancer.

AIM: To explore the role of salt-inducible kinase 2 (SIK2) on glucose and lipid metabolism in ovarian cancer (OC), so as to increase the understanding of potential inhibitors targeting SIK2 and lay a foundation for future precision medicine in OC patients. METHODS: We reviewed and summarized the regulation effect of SIK2 on glycolysis, gluconeogenesis, lipid synthesis, and fatty acids ß-oxidation (FAO) in OC, as well as the potential molecular mechanism and the prospects of potential inhibitors targeting SIK2 in future cancer treatments. RESULTS: Many pieces of evidence show that SIK2 is closed associated with glucose and lipid metabolism of OC. On the one hand, SIK2 enhances the Warburg effect by promoting glycolysis and inhibiting oxidative phosphorylation and gluconeogenesis, on the other hand, SIK2 regulates intracellular lipid metabolism through promoting lipid synthesis and FAO, all of which ultimately induces growth, proliferation, invasion, metastasis, and therapeutic resistance of OC. On this basis, SIK2 targeting may become a new solution for the treatment of a variety of cancer types including OC. The efficacy of some small molecule kinase inhibitors has also been demonstrated in tumor clinical trials. CONCLUSION: SIK2 displays significant effects in OC progression and treatment through regulating cellular metabolism including glucose and lipid metabolism. Therefore, future research needs to further explore the molecular mechanisms of SIK2 in other types of energy metabolism in OC, based on this to develop more unique and effective inhibitors.

The effects of incorporation of the counterparts and mimics of L-lysine on the antimicrobial activity, hemolytic activity, cytotoxicity and tryptic stability of antimicrobial peptide polybia-MPII.

Due to the limited effects of conventional antibiotics on the increasing emergence of drug-resistant bacteria and fungi, novel antimicrobial agents were urgently needed to alleviate this phenomenon. Nowadays, antimicrobial peptides are believed to be a promising candidate for a new generation of antimicrobial drugs. Antimicrobial peptide polybia-MPII (MPII) was first isolated from the venom of the social wasp Polybia paulista with a broad spectrum of antimicrobial activity. In the present study, the counterparts and mimics of cationic amino acids of Lys, such as Arg, His, Orn, Dab and Dap were employed to substitute Lys in the sequence of MPII. The effects of the incorporation of these amino acids on its antimicrobial activity, hemolytic activity, cytotoxicity, enzyme stability and therapeutic potential were explored. Our results showed that although the incorporation of Arg could improve its antimicrobial activity, there is no improvement in enzyme stability. The incorporation of His makes MPII exert its antimicrobial activity in a pH-dependent manner. Notably, incorporating Dap could effectively decrease its hemolytic activity and cytotoxicity and enhance its enzyme stability against trypsin. In conclusion, this study would provide an effective strategy to improve the bioavailability and metabolic stability of AMPs while decrease their hemolytic activity and cytotoxicity.

Cholesterol metabolism is decreased in patients with diminished ovarian reserve.

RESEARCH QUESTION: Does cholesterol metabolism differ in patients with diminished ovarian reserve (DOR) compared to patients with normal ovarian reserve (NOR)? DESIGN: The current research included 72 women with NOR and 86 women with DOR. Data on the cholesterol metabolism in granulosa cells of these women were analysed. RESULTS: On the day of human chorionic gonadotrophin injection, serum oestradiol and progesterone in the DOR group were significantly lower than in the control group (P < 0.001). There were no significant differences in serum concentrations of total cholesterol, triglyceride, high-density lipoprotein and low-density lipoprotein between the NOR and DOR groups. The cholesterol-regulated gene SCAP in granulosa cells from women with DOR was down-regulated (P = 0.024). Cholesterol synthesis and transport genes (e.g. IDI1, FDFT1, CYP51A1, SRB1 and STARD1) were also significantly decreased (P = 0.026, P = 0.044, P = 0.049, P = 0.004 and P < 0.001, respectively). In granulosa cells of patients with DOR, cholesterol-related substances such as coprostanone, 11A-acetoxyprogesterone and 17α-hydroxyprogesterone were significantly reduced (P = 0.0008, P = 0.0269, P = 0.0337, respectively). CYP19A1, a key steroidogenesis gene, was significantly reduced (P = 0.009). 17α-hydroxyprogesterone and oestradiol decreased (P = 0.004 and P = 0.039, respectively). CONCLUSION: Decreased cholesterol metabolism affecting steroid hormone synthesis in granulosa cells might be a possible mechanism for DOR.

Decreased fatty acids induced granulosa cell apoptosis in patients with diminished ovarian reserve.

PURPOSE: To investigate whether fatty acid changes in granulosa cells (GCs) underly the pathogenic mechanisms of diminished ovarian reserve (DOR). METHODS: GCs were obtained from patients with DOR (n = 70) and normal ovarian reserve (NOR, n = 70). Analysis of fatty acids changes in GCs was then analyzed. RESULTS: Patients with DOR had significantly lower levels of antral follicle count and anti-Mullerian hormone and higher levels of follicle-stimulating hormone compared with NOR patients (P < 0.001). The good-quality embryo rate was notably decreased in DOR patients (51.99 vs 39.52%, P < 0.05). A total of 15 significantly decreased fatty acids in GCs from patients with DOR. The ATP levels were markedly lower in DOR patients than in NOR patients (39.07 ± 12.89 vs 23.21 ± 13.69%, P < 0.05). Mitochondrial membrane potential decreased in DOR patients (P < 0.01). In GCs from DOR patients, the ß-oxidation genes (HADHA and ACSL) and DNA repair genes (PRKDC and RAD50) were significantly downregulated (P < 0.05). The γH2AX foci/nucleus ratio in DOR patients markedly increased relative to that of NOR patients (0.31 ± 0.03 vs 0.87 ± 0.07, P < 0.001). Meanwhile, the apoptosis rate of GCs was significantly higher in DOR patients (6.43 ± 2.11 vs 48.06 ± 6.72%, P < 0.01). CONCLUSION: GC apoptosis resulting from the decrease of fatty acids, and associated with reduced ATP production and DNA damage, may contribute to the pathogenic mechanisms responsible for DOR.

GNA14 stimulation of KLF7 promotes malignant growth of endometrial cancer through upregulation of HAS2.

BACKGROUND: Endometrial cancer (UCEC) is one of the most common gynecological malignancies. We previously found that overexpression of G protein α subunit 14 (GNA14) promoted UCEC growth. Krüppel-like factor 7 (KLF7) acts as an oncogene in various cancer types, whereas the connection between GNA14 and KLF7 in UCEC is unclear. We herein explored the involvement of GNA14/KLF7 in UCEC development. METHODS: Clinical relevance of GNA14, KLF7 and HAS2 in UCEC was analyzed from TCGA and by immunohistochemical staining. Knockdown and overexpression of indicated genes were conducted by transfecting the cells with siRNAs and lentivirus, respectively. mRNA and protein expression was detected by qRT-PCR and Western blot. CCK8, colony formation, cell cycle, apoptosis, transwell and wound healing were performed to check cell biology function in vitro. Tumor growth in nude mice was conducted to check in vivo function. RNA sequencing was used to determine dys-regulated genes. RESULTS: We demonstrated that GNA14 stimulated the expression of KLF7 in UCEC cells. There was a positive correlation between GNA14 and KLF7 in normal and UCEC tissues. In vitro, KLF7 promoted cell proliferation, colony formation, cell cycle progression, and migration of UCEC cells. Apoptosis was inhibited by KLF7. Xenografted tumorigenesis of UCEC cells was suppressed by KLF7 knockdown. Furthermore, RNA sequencing results showed that KLF7 regulated the expression of a large amount of genes, among which hyaluronan synthase 2 (HAS2) was downregulated in KLF7 knockdown cells. Based on TCGA database and immunoblotting assays, KLF7 positively regulated HAS2 in UCEC cells and tissues. Lastly, knockdown of HAS2 reversed the oncogenic role of KLF7 on UCEC cell proliferation, migration, and xenografted tumor development. CONCLUSION: Taken together, we reveal that GNA14/KLF7/HAS2 signaling cascade exerts tumor promoting function during UCEC development.

The introduction of L-phenylalanine into antimicrobial peptide protonectin enhances the selective antibacterial activity of its derivative phe-Prt against Gram-positive bacteria.

Protonectin was a typical amphiphilic antimicrobial peptide with potent antimicrobial activity against Gram-positive and Gram-negative bacteria. In the present study, when its eleventh amino acid in the sequence was substituted by phenylalanine, the analog named phe-Prt showed potent antimicrobial activity against Gram-positive bacteria, but no antimicrobial activity against Gram-negative bacteria, indicating a significant selectivity between Gram-positive bacteria and Gram-negative bacteria. However, when Gram-negative bacteria were incubated with EDTA, the bacteria were susceptible to phe-Prt. Next, the binding effect of phe-Prt with LPS was determined. Our result showed that LPS could hamper the bactericidal activity of phe-Prt against Gram-positive bacteria. The result of zeta potential assay further confirmed the binding effect of phe-Prt with LPS for it could neutralize the surface charge of E. coli and LPS. Then, the effect of phe-Prt on the integrity of outer membrane of Gram-negative bacteria was determined. Our results showed that phe-Prt had a much weaker disturbance to the outer membrane of Gram-negative bacteria than the parent peptide protonectin. In summary, the introduction of L-phenylalanine into the sequence of antimicrobial peptide protonectin made phe-Prt show significant selectivity against Gram-positive bacteria, which could partly be attributed to the delay effect of LPS for phe-Prt to access to cell membrane. Although further study is still needed to clarify the exact mechanism of selectivity, the present study provided a strategy to develop antimicrobial peptides with selectivity toward Gram-positive and Gram-negative bacteria.

Cu2+ reduces hemolytic activity of the antimicrobial peptide HMPI and enhances its trypsin resistance.

Nowadays, drug-resistant microbes are becoming a serious clinical problem threatening people's health and life. Antimicrobial peptides (AMPs) are believed to be potential alternatives of conventional antibiotics to combat the threat of drug-resistant microbes. However, the susceptibility of AMPs toward proteases is one of the major problems limiting their clinical use. In the present study, we reported the effect of Cu2+ on the bioactivity of AMP HMPI. We found that the addition of Cu2+ could improve the protease resistance of AMP HMPI without affecting its bioactivity. Notably, after the binding of Cu2+ with HMPI, the hemolytic activity of HMPI was greatly decreased. In addition, our results also demonstrated that the addition of Cu2+ increased the production of reactive oxygen species in the fungal cells, which may be a supplement for the antifungal activity of HMPI. In conclusion, the introduction of Cu2+ may provide an inorganic strategy to improve the stability and decrease the hemolytic activity of AMP HMPI, while maintaining its antifungal activity.

A meta-analysis of the effects of intramuscular and intravenous injection of oxytocin on the third stage of labor.

BACKGROUND: Clinical studies and trials have shown that oxytocin can effectively reduce postpartum bleeding, whether by intramuscular (IM) injection or intravenous (IV) injection. These two methods are widely used in the prevention and treatment for the third stage of childbirth. However, it is unclear whether the subtle differences between the mode of these routes have any effect on maternal outcomes. OBJECTIVES: To systematically evaluate the efficacy and safety of oxytocin administered intramuscularly or intravenously for prophylactic management of the third stage of labor after vaginal birth. METHODS: Computerized retrieval of PubMed, the Cochrane Library, Web of Science, Embase, and ClinicalTrials.gov was conducted to collect randomized controlled trials (RCT) on the effects of IM and IV oxytocin on the third stage of labor. After independent literature screening, data extraction and evaluation of the bias risk of included studies by two evaluators, RevMan 5.3 software was used for a meta-analysis. RESULTS: Six studies with 7734 women were included in this study. Meta-analysis results showed that: the severe postpartum hemorrhage (PPH) rate [risk ratio (RR) 1.54, 95% confidence interval (95% CI) 1.08-2.20, P = 0.02], PPH rate (RR 1.31, 95% CI 1.11-1.55, P = 0.001), incidence of blood transfusion (RR 2.30, 95% CI 1.35-3.93, P = 0.002) and the need of manual removal of placenta (RR 1.44, 95% CI 1.05-1.96, P = 0.02) for IM group were higher than IV group, but there were no significant differences in the use of additional uterotonics (P = 0.31) and the incidence of serious maternal morbidity and adverse effects between two groups. None of the included studies reported maternal death. CONCLUSION: For clinical practice, intravenous injection oxytocin 10 IU may be a good, safe option in the management of the third stage of labor. Medical conditions, available resources, adverse effects, and women' s preferences should also be considered. If an IV line is already in place at delivery, IV administration may be preferable to IM injection.

Female age affects the utility of sperm DNA fragmentation in predicting IVF and ICSI outcomes.

RESEARCH QUESTION: The aim of this study was to investigate how female age affects the predictive effect of sperm DNA fragmentation index (DFI) on clinical outcomes with assisted reproductive technology. DESIGN: A total of 2371 patients, comprising 2115 men with a normal DFI (≤30), 256 men with a high DFI (>30) and women of different ages, were recruited and investigated. All patients had normal chromosome karyotypes and were undergoing their first fresh IVF or intracytoplasmic sperm injection (ICSI) cycles. Clinical outcomes were analysed according to the two DFI groups and female age ≤30 and >30 years. Binary logistic regression analysis was performed to identify factors associated with clinical outcome. RESULTS: The proportion of couples with at least one good-quality embryo in the DFI ≤30 group was higher than that in the DFI >30 group. When female age exceeded 30 years, clinical pregnancy rate and the proportion of couples with good-quality embryos in the DFI >30 group were lower compared with DFI ≤30; however, there were no differences in outcomes for female age ≤30 years according to DFI. When DFI >30, the cut-off value of female age was 30.5 for detecting clinical pregnancy; the sensitivity was 62.0%, and the specificity was 63.6%. Clinical pregnancy rate and proportion of couples with good-quality embryos were lower in the DFI >30 versus DFI ≤30 group with a female age above 30 years for IVF but not for ICSI. CONCLUSION: Female age has a negative effect and should be considered in predicting the effects of sperm DNA fragmentation on pregnancy outcomes.

Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a.

Angiogenesis plays crucial roles in various physiological processes including wound healing and tissue repair. It requires a tight interaction between endothelial cells and their surrounding environment. Mesenchymal stem cells (MSCs), one of the non-endothelial cell types present in the perivascular environment, have been shown to secret exosomes to modulate intercellular communications between MSCs and their target cells. In this study, we initially isolated exosomes secreted by human adipose-derived MSCs (adMSC-Exo) and examined their roles in angiogenesis. We found that adMSC-Exo could be taken up by endothelial cells and significantly promote angiogenesis in vitro and in vivo Further study showed that miR-125a was enriched in adMSC-Exo, and repressed the expression of the angiogenic inhibitor delta-like 4 (DLL4) by targeting its 3' untranslated region. Additionally, adMSC-Exo and its exosomal transferred miR-125a could repress DLL4 expression and modulate endothelial cell angiogenesis through promoting formation of endothelial tip cells. In conclusion, our study indicates that adMSC-Exo can transfer miR-125a to endothelial cells and promote angiogenesis by repressing DLL4. adMSC-Exo, as a pro-angiogenic factor, might be a promising candidate for therapeutical tissue repair.

Original endomorphin-1 analogues exhibit good analgesic effects.

A new class of endomorphin-1 analogues was synthesized by combining successful chemical modifications including N-terminal guanidino modification, Phe4 was chlorinated, D-Ala-Gly Substituted L-Pro2. Their bioactivities were measured by radioligand binding assay, metabolic stability and the tail-flick test. In radioligand binding assays, analogue GAGPC (Nα-Amidino-Tyr-D-Ala-Gly-Trp-p-Cl-Phe-NH2), shown a µ-opioid receptor affinity about 1.42-fold higher and a 2.51-fold higher δ-opioid receptor affinity than EM-1. In the metabolic stability assays, GAGPC had the longest half-lives which was 284min and 53-fold higher than that of EM-1. In the tail-flick test in mice, GAGPC chloride modification increases the lipid content of the drug, thus increases the permeability of the blood brain barrier, and has a higher analgesic activity. It might be of importance in potential application as drug candidates as analgesic.

Original endomorphin-1 analogues exhibit good analgesic effects with minimal implications for human sperm motility.

To search a novel analgesic characterizes the effects on human sperm motility as minimal as possible. A new class of endomorphin-1 (EM-1) analogues was synthesized by combining successful chemical modifications including N-terminal guanidino modification, Phe4 was chlorinated, replaced of l-Pro2-Trp3 by d-Ala2-Gly3 or d-Pro2-Gly3 at position 2 and 3. Their bioactivities were measured by radioligand binding assay, metabolic stability, antinociception activity and sperm motility effects. In radioligand binding assays, analogue GAGP shown a µ-opioid receptor affinity about 17.7-fold higher and a 57.3-fold higher δ-opioid receptor affinity than EM-1. In the metabolic stability assays, GAGP had the longest half-lives and 16.6-fold higher than EM-1. In the tail-flick test in mice, GAGP showed the best analgesia. In sperm motility assays, the group of GAGP (10-5, 10-7mol/L) decreased of the percentage of a+b grade, and no significant when compared with initial value. In GAGP (10-6mol/L) group, sperm motility was progressively increased, although it was not statistically significant. But at the groups of morphine (10-7mol/L) and GAGD (10-7mol/L), these caused significant reduction between 0 and 90 min. We found that analogues GAGP, activating µ-opioid receptor and partial δ-opioid receptor, exhibit good analgesic effects with minimal implications for human sperm motility. It might be important in potential application as drug candidates of analgesic without implications for human sperm motility.