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MicroRNAs (miRNAs) are of importance to chronic heart failure (CHF). However, the relevance of the exosomal miRNAs produced during CHF remains unknown. Our purpose here was to examine the relevance of exosomal miR-1246 released from human umbilical cord mesenchymal stem cell (hucMSC) during CHF and the mechanism of action. Cardiac function, myocardial infarction area, apoptosis, and angiogenesis were all evaluated in a CHF rat model following treatment with hucMSC-derived exosomes (hucMSC-Exos). H9C2 and human umbilical vascular endothelial cells (HUVECs) were subjected to oxygen and glucose deprivation and exosome treatment to quantify the cell proliferation and apoptosis in H9C2 cells and the tube formation capacity of the HUVECs. A dual-luciferase activity reporter assay was conducted to validate the interaction between miR-1246 and serine protease 23 (PRSS23). HucMSCs treatment led to a reduction in H9C2 apoptosis and an increase in HUVEC angiogenesis, which were mitigated when hucMSCs were treated with an miR-1246 inhibitor. We also confirmed that PRSS23 is a putative target of miR-1246 and that miR-1246 attenuated hypoxia-induced myocardial tissue damage by targeting PRSS23 and inhibiting the activation of the Snail/α-SMA signaling. Our findings suggest that exosomal miR-1246 from hucMSCs protects the heart from failure by targeting PRSS23. This article is protected by copyright. All rights reserved.

Chronic active Epstein-Barr virus (CAEBV) infection is a rare disease with a high mortality rate. Our study aimed to summarize the clinicopathological characteristics of CAEBV infection in adults and improve knowledge of the disease. Data for 19 adult patients with CAEBV confirmed at our hospital from January 2010 to December 2019 were collected retrospectively. There were 14 males and 5 females, and the median age was 33 years (range 14-83). The main clinical manifestations included recurrent fever (84.2%, 16/19), splenomegaly (89.5%, 17/19), hepatomegaly (73.6%, 14/19), lymphadenopathy (42.1%, 8/19), abnormal liver function (78.9%, 15/19), hemopenia (94.7%, 18/19), and hemophagocytosis (52.6%, 10/19). A total of 22 specimens were collected from 19 patients for histopathology. Most of the biopsy specimens showed lymphocyte infiltration. Immunohistochemical staining and EBV-encoded small RNA (EBER) in situ hybridization were performed for 14 of the 22 samples. CD3 and CD20 staining were positive, with more CD3-positive cells than CD20-positive cells (100%, 14/14), and EBER in situ hybridization was positive in most cases (85.7%, 12/14). More than half of TCR gene rearrangement tests showed monoclonal rearrangement (66.6%, 4/6). Mortality was high, with most CAEBV patients dying during the period from diagnosis to the end of follow-up (12/19, 63%); the median survival time was only 20.75 months. Based on limited data, we consider that CAEBV is a disease with different ages of onset and is a complex and heterogeneous syndrome with features of both immunodeficiency and malignant neoplasms. Furthermore, the prognosis of adult-onset CAEBV appears to be very poor.

To explore whether elevated luteinizing hormone (LH) level before trigger means premature LH surge in advanced aged women undergoing mild ovarian stimulation.To retrospectively analyze 235The dynamic change of LH level during stimulation; the proportion of an elevated LH level defined as10 IU/L on trigger day; the proportion of premature ovulation in each group.Serum LH level increased early in Group 2 and Group 3 and remained significantly higher than that in Group 1 during stimulation. In a sequence of three groups, the proportion of elevated LH levels before the trigger was 11.84, 43.8, and 37.21% (Elevated LH level before trigger does not mean premature LH surge in women more than 35 years old with POR undergoing mild ovarian stimulation with clomiphene or tamoxifen.

Data from in vitro and animal studies support the preventive effect of tea (Camellia sinensis) against colorectal cancer. Further, many epidemiologic studies evaluated the association between tea consumption and colorectal cancer risk, but the results were inconsistent. We conducted a meta-analysis of prospective cohort studies to systematically assess the association between tea consumption and colorectal cancer risk. A comprehensive literature review was conducted to identify the related articles by searching PubMed and Embase up to June, 2019. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using a fixed effect model. Twenty cohort articles were included in the present meta-analysis involving 2,068,137 participants and 21,437 cases. The combined RR of colorectal cancer for the highest vs. lowest tea consumption was determined to 0.97 (95% CI 0.94–1.01) with marginal heterogeneity (I2 = 24.0%, P = 0.093) among all studies. This indicated that tea consumption had no significant association with colorectal cancer risk. Stratified analysis showed that no significant differences were found in all subgroups. We further conducted the gender-specific meta-analysis for deriving a more precise estimation. No significant association was observed between tea consumption and colorectal cancer risk in male (combined RR = 0.97; 95% CI 0.90–1.04). However, tea consumption had a marginal significant inverse impact on colorectal cancer risk in female (combined RR = 0.93; 95% CI 0.86–1.00). Further, we found a stronger inverse association between tea consumption and risk of colorectal cancer among the female studies with no adjustment of coffee intake (RR: 0.90; 95% CI 0.82–1.00, P 0.05). Our finding indicates that tea consumption has no significant impact on the colorectal cancer risk in both genders combined, but gender-specific meta-analysis shows that tea consumption has a marginal significant inverse impact on colorectal cancer risk in female.

ObjectiveNonalcoholic fatty liver disease (NAFLD) is becoming a global public health challenge. A convenient NAFLD indicator will greatly facilitate risk appraisal and prevention. As a readily available and inexpensive hematological index in routine clinical examinations, red blood cells (RBCs) are gaining increasing attention in many diseases, such as metabolic syndrome, but their association with NAFLD is unknown.MethodsThis health management cohort study included 27,112 subjects (17,383 non-NAFLD and 9,729 NAFLD) with up to 5 years of follow-up (median 2.8 years). NAFLD was diagnosed by ultrasonography. NAFLD severity was categorized as mild, moderate, or severe. The generalized estimation equation (GEE), an extension of generalized linear models that allows for analysis of repeated measurements, was used to analyze the association between RBC count and NAFLD.ResultsOverall, 4,332 of 17,383 (24.9%) subjects without NAFLD at baseline developed NAFLD. Incident NAFLD risk was positively associated with RBC count. After adjustment for hemoglobin and other confounders, the risk of incident NAFLD was 21%, 32%, and 51% higher in the second, third, and fourth RBC count quartiles, respectively, than in the lowest quartile. In 1,798 of 9,476 (19.0%) subjects with NAFLD at baseline, the severity of NAFLD increased. NAFLD progression risk increased progressively as RBC count increased (P for trend 12 cells/L) increase in RBC count was associated with a 53% [OR 1.53 (95% CI 1.32-1.77)] increased risk for NAFLD progression.ConclusionsElevated RBC count was independently associated with a high risk of NAFLD incidence and progression. This finding revealed a convenient NAFLD risk indicator.

PurposeTo determine the impact of ovarian endometrioma per se on in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes.MethodsThis retrospective study was conducted using two groups. The endometrioma group consisted of 862 women with infertility who had ovarian endometriomas and underwent their first ovarian stimulation for IVF/ICSI treatment between January 2011 to December 2019 at a public university hospital. A non-endometrioma comparison group, comprising 862 women with other infertility factors, was matched according to maternal age, body mass index (BMI), and infertility duration. Ovarian reserve and response and IVF/ICSI and pregnancy outcomes between the two groups were analyzed. Multivariate logistic regression (MLR) analysis was conducted on the basis of clinical covariates assessed for their association with live birth.ResultsThe results showed that significantly lower antral follicle count (AFC), anti-Müllerian hormone (AMH), ovarian sensitivity index (OSI), oocyte maturation and fertilization rates, blastocyst rate, number of oocytes retrieved, and available embryos were found in women with endometrioma compared with the control, respectively (P < 0.05). The cumulative live birth rate per patient in women with endometrioma was lower than that of women without endometrioma (39.32% vs. 46.87%, P = 0.002). In women with endometrioma, those who underwent surgical intervention prior to IVF/ICSI treatment had higher maturation (86.03% vs. 83.42%, P = 0.003), fertilization (78.16% vs. 74.93%, P = 0.004), and top-quality embryo rates (42.94% vs. 39.93%, P = 0.097) but had fewer oocytes retrieved (8.01 ± 5.70 vs. 9.12 ± 6.69, P = 0.013) than women without surgery. However, live birth rates were comparable between women with endometrioma and women in the control group, regardless of whether they had a prior history of ovarian surgery. MLR analysis showed no correlation between endometrioma per se and live birth after being adjusted for number of top-quality embryos transferred and stage of embryo transfer.ConclusionsThe data from this study supported the conclusion that ovarian endometrioma negatively impacts oocyte quality and quantity, but not overall pregnancy outcomes, in women undergoing IVF/ICSI treatment. Endometrioma lowers the cumulative live birth rate by decreasing the number of embryos. Surgical excision of endometrioma prior to IVF/ICSI can partly improve oocyte maturation and fertilization rates but not pregnancy outcomes.

Background Circadian rhythm is an important player for reproduction. Rev-erbα, a significant clock gene, is involved in regulating cell differentiation, inflammation and metabolism. Macrophage polarization plays crucial roles in immune tolerance at the maternal-fetus interface, which also modulates the initiation and resolution of inflammation. Alteration of macrophage polarization induces adverse pregnancy outcomes such as infertility, recurrent spontaneous abortion and preterm labor. Results Decidual macrophages from LPS-induced mice abortion model displayed M1-like bias, accompanied by decreased expression of Rev-erbα. SR9009, an agonist of Rev-erbα, may reduce lipopolysaccharide (LPS)-induced M1 polarization of macrophages via activation of PI3K but not NF-κB signaling pathway. Furthermore, SR9009 could reduce M1-like polarization of decidual macrophages induced by LPS and attenuate LPS-induced resorption rates in mice model. Conclusions Both in vivo and in vitro experiments demonstrated that the pharmacological activation of Rev-erbα using SR9009 could attenuate the effect of LPS on macrophage polarization and protect pregnancy. This study may provide a potential therapeutic strategy for miscarriage induced by inflammation.

ObjectiveMenopause contributes to renal dysfunction in women, which is generally attributed to estrogen withdrawal. In addition to decreased estrogen level, serum follicle-stimulating hormone (FSH) level increases after menopause. This study investigated the association between high circulating FSH level and renal function in post-menopausal women.MethodsThis observational cross-sectional study included 624 pre-menopausal, 121 peri-menopausal, and 2540 post-menopausal women. The levels of female sex hormones were examined by chemiluminescence and indices of renal function were measured using a clinical chemistry analyzer. The post-menopausal women were grouped into quartiles according to serum FSH levels.ResultsRenal function progressively declined from pre-menopause to peri-menopause to post-menopause, which was accompanied by increasing serum FSH level. In post-menopausal women, serum creatinine level increased with increasing FSH quartile, which was accompanied by a decrease in estimated glomerular filtration rate (eGFR) (p for trend 2) and chronic kidney disease (CKD; eGFR 2) increased (p for trend ConclusionsA high circulating FSH level is an independent risk factor for renal dysfunction in women after menopause. Additionally, aging may aggravate the association of high FSH levels with reduced renal function in post-menopausal women.

Centromere proteins (CENPs) are the main constituent proteins of kinetochore, which are essential for cell division. In recent years, several studies have revealed that several CENPs were aberrantly expressed in hepatocellular carcinoma (HCC). However, numerous centromere proteins have not been studied in HCC. In this study, we used databases of Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), the Kaplan-Meier Plotter, cBioPortal, the Human Protein Atlas (HPA), and TIMER (Tumor Immune Estimation Resource) and immunohistochemical staining of clinical specimens to investigate the expression of 15 major centromere proteins in HCC to evaluate their potential prognostic value. We found that the mRNA levels of 4 out of 15 centromere proteins (CENPL, CENPQ, CENPR, and CENPU) were significantly higher in HCC than in normal tissues, and their mRNA levels were associated with the tumor stages ( p values < 0.01). Patients with higher mRNA levels of CENPL had poorer overall survival, progression-free survival, relapse-free survival, and disease-specific survival ( p values < 0.05). Furthermore, the higher levels of CENPL mRNA were associated with worse overall survival in males without hepatitis virus infection ( p values < 0.05). The protein expression level of CENPL in human HCC tissue was higher than that in normal liver tissue. In addition, the expression of CENPL was positively correlated with the levels of the tumor-infiltrating lymphocytes. The results suggest that the high mRNA expression of CENPL may be a potential predictor of prognosis in HCC patients.

Diabetic retinopathy (DR) remains high incidence and accounts for severe impact on vision in diabetics, but its mechanism is still poorly understood. Abnormal migration and proliferation of endothelial cells (ECs) drive neovascular retinopathies, which has an important role in promoting the occurrence and development of DR. In this study, we designed and synthesized a series of PEDF-derived peptides as angiogenesis inhibitors. Especially, compound G24 significantly inhibited the cell proliferation in VEGF-activated human umbilical vein endothelial cells (HUVECs) with IC50 values of 2.88 ± 0.19 μM. Further biological evaluation demonstrated that compound G24 exhibited strong inducing-effects on cell apoptosis and internalization of 67LR, and advanced inhibitory potency in cell migration and angiogenesis formed by HUVECs in vitro. In summary, the optimal compound G24 as a novel angiogenesis inhibitor showed the potentiality in the further research for the treatment for DR.

Do frozen embryo transfer (FET) cycles following long-term gonadotrophin-releasing hormone agonist (GnRHa) pretreatment have better pregnancy outcomes than fresh embryo transfer cycles with long or ultra-long GnRHa protocol in these patients?This study included 537 women with adenomyosis divided into three groups: (Group A) FET cycles following long-term GnRHa pretreatment (192 patients); (Group B) fresh embryo transfer cycles with the ultra-long GnRHa protocol (241 patients); (Group C) fresh embryo transfer cycles with the long GnRHa protocol (104 patients).The total gonadotrophin dose and stimulation duration were significantly lower in Group A than in Groups B and C. The implantation and live birth rates were significantly higher in Group A than in Groups B and C. In the long-term GnRHa pretreatment and FET treatment of Group A, implantation (odds ratio [OR] 1.729, 95% confidence interval [CI] 1.073-2.788, P = 0.025), clinical pregnancy (OR 1.665, 95% CI 1.032-2.686, P = 0.037) and live birth rates (OR 1.694, 95% CI 1.045-2.746, P = 0.033) increased and miscarriage rate (OR 0.203, 95% CI 0.078-0.530, P = 0.001) decreased when compared with Group C. Comparison of Groups A and B showed that with the long-term GnRHa pretreatment, FET was a protective factor for live birth rate (OR 1.350, 95% CI 1.017-1.792, P = 0.038).FET following long-term GnRHa pretreatment has a better IVF/intracytoplasmic sperm injection outcome, and a potential benefit in terms of a lower gonadotrophin dose, and a shorter stimulation duration than fresh embryo transfer combined with a long or ultra-long GnRHa protocol.

Background Nanodiamonds (NDs) have been demonstrated to have bactericidal activity on several microorganisms and can be used in various kinds of dental materials. NDs are potential candidates for antibacterial dental materials. However, the possible inhibitory effect of NDs on oral pathogenic bacteria is largely unknown. This study was performed to investigate the inhibitory effects of carboxylated nanodiamond (cND) on Streptococcus mutans. Methods Fourier transform infrared spectroscopy was used to confirm carboxyl groups on the surface of commercial cND. The inhibitory effect of serially diluted cND on S. mutans was evaluated by spectrophotometry and plating methods. Escherichia coli was treated as a positive control in spectrophotometry. Chlorhexidine was used as a positive control in plating methods. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were employed to confirm the antibacterial activity of cND. Results The results showed that cND exhibited a significant inhibitory effect on S. mutans. For S. mutans, the minimum inhibitory concentration was 4 μg/ml and the minimum bactericidal concentration was 16 μg/ml. SEM and TEM results indicated that cND functioned as an antibacterial agent, likely due to its ability to disrupt the cell membrane of S. mutans. Conclusion In conclusion, these findings demonstrated an inhibitory effect of cND on S. mutans and suggest its use as a potential antibacterial dental material., Nanodiamonds have been demonstrated to have bactericidal activity on several microorganisms and can be used in various kinds of dental materials. Nanodiamonds are potential candidates for antibacterial dental materials. However, the possible inhibitory effect of nanodiamonds on oral pathogenic bacteria is largely unknown. The present study was performed to investigate the inhibitory effects of carboxylated nanodiamond (cND) on Streptococcus mutans (S. mutans). Fourier transform infrared spectroscopy was used to confirm carboxyl groups on the surface of commercial cND. The inhibitory effect of serially diluted cND on S. mutans was evaluated by spectrophotometry and plating methods. Escherichia coli was treated as a positive control in spectrophotometry. Chlorhexidine was used as a positive agent control in plating methods. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were employed to confirm the antibacterial activity of cND. The results showed that cND exhibited a significant inhibitory effect on S. mutans. For S. mutans, the minimal inhibitory concentration (MIC) was 4 μg/ml, and the minimum bactericidal concentration (MBC) was 16 μg/ml. SEM and TEM results indicated that cND functioned as an antibacterial agent, likely due to its ability to disrupt the cell membrane of S. mutans. In conclusion, these findings demonstrated an inhibitory effect of cND on S. mutans and suggest its use as a potential antibacterial dental material.

Therapeutic inhibition of hypoxia-inducible factor-1alpha (HIF-1α) action has emerged as a potential approach for managing several diseases, including myopia. Herein, we analyzed the role of HIF-1α in the progression of pathologic myopia by regulating the miR-150-5p/LAMA4/p38 MAPK axis. Microarray-based gene expression profiling of pathologic myopia was employed to identify differentially expressed genes. Human scleral fibroblasts (HSFs) were cultured under the hypoxic conditions. Interaction among HIF-1α, miR-150-5p, and LAMA4 was identified. Gain- and loss-of-function experiments were performed in hypoxia-exposed HSFs to evaluate the effect of the HIF-1α/miR-150-5p/LAMA4/p38 MAPK axis on the extracellular matrix (ECM) degradation of HSFs and the subsequent pathologic myopia progression. Increased LAMA4 but decreased miR-150-5p was found in serum sample of pathologic myopia patients. HIF-1α and LAMA4 were abundantly expressed, and p38 MAPK was activated while miR-150-5p was weakly expressed in hypoxia-exposed HSFs. HIF-1α was enriched in the promoter region of miR-150-5p and downregulated its expression, thus repressing the ECM degradation of HSFs as shown by increased COL1A1 and TIMP-2 and reduced MMP2. In addition, LAMA4 was a downstream target of miR-150-5p and under the negative regulation by miR-150-5p. Overexpression of miR-150-5p promoted the ECM degradation of HSFs by inhibiting LAMA4 expression and p38 MAPK signaling pathway. However, upregulation of LAMA4 reversed the promoting effect of miR-150-5p on ECM degradation of HSFs. Overall, our findings suggest that HIF-1α can decline miR-150-5p expression and facilitate LAMA4-mediated p38 MAPK signaling pathway activation, thus arresting ECM degradation of HSFs and eventually inducing pathologic myopia.

Problem Circadian rhythms are involved not only in the repair and regeneration of the immune system, but may also be associated with regulation of inflammation and immune responses. Rev-erbα could constitute a link between immunity and circadian rhythms since it is a transcription factor that regulates circadian rhythms and has functions in multiple physiological and pathological processes. Decidual macrophages (dMφs) play crucial roles in immune balance at the maternal-fetal interface, and abnormal macrophage polarization is related to adverse pregnancy outcomes, such as infertility, recurrent spontaneous abortion, and preterm labor. However, whether Rev-erbα could modulate the polarization of macrophages is unknown. Methods of study In this study, we analyzed the phenotype of dMφs and the expression of Rev-erbα in dMφs from normal pregnancies and miscarriages. The effect of Rev-erbα on macrophage polarization was evaluated by its knockdown or pharmacological activation. The mechanism by which the Rev-erbα agonist SR9009 regulates macrophage polarization was also estimated. Results A type-1 macrophage (M1)-like dominance was observed in dMφs from human miscarriages, with a decreased expression of Rev-erbα compared to that from normal pregnancies. Rev-erbα knockdown promoted M1 polarization in macrophages differentiated from the THP1 cell line, whereas pharmacological activation of Rev-erbα by SR9009 induced type-2 macrophage (M2)-like polarization in dMφs. Furthermore, we found that SR9009 induced M2 polarization in macrophages differentiated from the U937 cell line via the PI3K/Akt signaling pathway. Conclusion Rev-erbα may play an essential role in macrophage polarization. These findings might help elucidate the role of Rev-erbα in regulating the differentiation and functions of macrophages and suggest a therapeutic target for pregnancy loss and pregnancy complications.

ObjectiveThis study aimed to compare the ultra-long gonadotropin-releasing hormone agonist (GnRH-a) protocol and the long GnRH-a protocol during in vitro fertilization (IVF) or intracytoplasmic sperm (ICSI) treatment on fertility outcomes in women with adenomyosis.Materials and MethodsThis study was a retrospective cohort study. From January 2011 to May 2018, a total of 371 fresh IVF/ICSI cycles were included. Among the cycles included, 237 cycles of 212 women underwent the ultra-long GnRH-a protocol, while 134 cycles of 116 women underwent the long GnRH-a protocol. The rates of implantation, clinical pregnancy per embryo transfer, live birth, and early miscarriage were estimated between the compared protocols.ResultsIn the study, the early miscarriage rate in women undergoing the ultra-long GnRH-a protocol was significantly lower than those undergoing the long GnRH-a protocol (12.0% versus 26.5%, p = 0.045), whereas the differences in the rates of biochemical pregnancy, implantation, clinical pregnancy, and live birth in women between the two groups showed no statistical significance. The pregnancy outcomes were also sub-analyzed according to the adenomyotic region (diffuse and focal). As for diffuse adenomyosis, the rates of clinical pregnancy and live birth in women undergoing the ultra-long GnRH-a protocol were significantly higher than those undergoing the long GnRH-a protocol (55.3% versus 37.9%, p = 0.025; 43.4% versus 25.9%, p = 0.019, respectively). However, pregnancy outcomes showed no difference between the two protocols in women with focal adenomyosis.ConclusionsThe ultra-long GnRH-a protocol during IVF/ICSI improves pregnancy outcomes in women with adenomyosis, especially in women with diffuse adenomyosis when compared with the long GnRH-a protocol.

Background The aim of the present study was to investigate whether painless labor with patientcontrolled epidural analgesia (PCEA) has a protective effect on pelvic floor function. And to observe if there was any difference in the effect of painless labor with PCEA versus vaginal delivery on postpartum shortterm pelvic floor function. Methods All women who delivered at the hospital's obstetric department during June 2016 to October 2018 were included in the study. They were divided according to delivery mode: painless labor with PCEA [group A (observation group), n=27], and vaginal delivery [group B (control group), n=36]. Pelvic floor function was assessed at postpartum 7 weeks. Results Groups A and B showed no significant difference in the total score at postpartum 6-8 weeks. However, group A showed lower pelvic floor muscle tone at rest and significantly higher muscle strength scores than group B. Both the pre-rest and post-rest phase muscle strength was stronger than in group B (P=0.039 and P=0.016, respectively). There was no significant difference in pelvic floor muscle strength between analgesia and non-analgesia groups, or between episiotomy and non-episiotomy recipients. Conclusions Painless labor with PCEA reduced both pain during the delivery and injury to the pelvic floor. It had protective effect on the pelvic floor muscles.

Cell‐based bone tissue engineering techniques utilize both osteogenic cells and biomedical materials, and have emerged as a promising approach for large‐volume bone repair. The success of such techniques is highly dependent on cell adhesion, spreading, and osteogenic activities. In this study, we investigated the effect of co‐administration of all‐trans retinoic acid (ATRA) and human salivary peptide histatin‐1 (Hst1) on the spreading and osteogenic activities of pre‐osteoblasts on bio‐inert glass surfaces. Pre‐osteoblasts (MC3T3‐E1 cell line) were seeded onto bio‐inert glass slides in the presence and absence of ATRA and Hst1. Cell spreading was scored by measuring surface areas of cellular filopodia and lamellipodia using a point‐counting method. The distribution of fluorogenic Hst1 within osteogenic cells was also analyzed. Furthermore, specific inhibitors of retinoic acid receptors α, β, and γ, such as ER‐50891, LE‐135, and MM‐11253, were added to identify the involvement of these receptors. Cell metabolic activity, DNA content, and alkaline phosphatase (ALP) activity were assessed to monitor their effects on osteogenic activities. Short‐term (2 h) co‐administration of 10 μm ATRA and Hst1 to pre‐osteoblasts resulted in significantly higher spreading of pre‐osteoblasts compared to ATRA or Hst1 alone. ER‐50891 and LE‐135 both nullified these effects of ATRA. Co‐administration of ATRA and Hst1 was associated with significantly higher metabolic activity, DNA content, and ALP activity than either ATRA or Hst1 alone. In conclusion, co‐administration of Hst1 with ATRA additively stimulated the spreading and osteogenicity of pre‐osteoblasts on bio‐inert glass surfaces in vitro., Adhesion and spreading of osteogenic cells are indispensable for initiation of bone regeneration. We showed that the co‐administration of all‐trans retinoic acid (ATRA) and human salary histatin‐1 (Hst1) resulted in significantly enhanced spreading, metabolic activity, proliferation (DNA content), and osteogenic differentiation (alkaline phosphatase activity) of pre‐osteoblasts on bio‐inert surfaces, thus bearing a promising application potential in bone tissue engineering.

The association between whole blood viscosity (WBV) and metabolic syndrome (MetS) is still scarcely investigated in the population-based prospective cohort. We aim to explore the longitudinal effect of WBV on MetS, and to verify whether WBV measures can be used as early predictors for MetS. The longitudinal cohort consisted of 3,508 adults (2,350 males and 1,158 females) who visited the health check-up system twice. WBV were measured at four shear rate (200, 50, 10 and 1 s-1), and their values were classified into quartiles. Multivariate Cox models were used to estimate the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) in men and women, respectively. A total of 444 (12.66%) incident MetS were observed at follow-up period. The incidences of MetS significantly increased with increasing quartiles of WBVs at all of the shear rate in men. After adjusting for baseline age, smoking, obesity, hypertension, hyperglycemia, and hyperlipidemia status, all of the WBV measures were significantly associated with incident MetS in men, and the HRs showed clear increasing trend across the quartiles of baseline WBVs. There were no significant association between WBVs and incident MetS in women. These findings suggest that MetS has a hemodynamic basis, and WBVs could be used as independent early predictor for MetS in men.

STUDY QUESTION Does an artificially induced FSH surge at the time of hCG trigger improve IVF/ICSI outcomes? SUMMARY ANSWER An additional FSH bolus administered at the time of hCG trigger has no effect on clinical pregnancy rate, embryo quality, fertilization rate, implantation rate and live birth rate in women undergoing the long GnRH agonist (GnRHa) protocol for IVF/ICSI. WHAT IS KNOWN ALREADY Normal ovulation is preceded by a surge in both LH and FSH. Few randomized clinical trials have specifically investigated the role of the FSH surge. Some studies indicated that FSH given at hCG ovulation trigger boosts fertilization rate and even prevents ovarian hyperstimulation syndrome (OHSS). STUDY DESIGN, SIZE, DURATION This was a randomized, double-blinded, placebo-controlled trial conducted at a single IVF center, from June 2012 to November 2013. A sample size calculation indicated that 347 women per group would be adequate. A total of 732 women undergoing IVF/ICSI were randomized, using electronically randomized tables, to the intervention or placebo groups. Participants and clinical doctors were blinded to the treatment allocation. PARTICIPANTS/MATERIALS, SETTING, METHODS Patients aged ≤42 years who were treated with IVF/ICSI owing to tubal factor, male factor, unexplained, endometriosis and multiple factors were enrolled in this trial. Subjects all received a standard long GnRHa protocol for IVF/ICSI and hCG 6000–10 000 IU to trigger oocyte maturation. A total of 364 and 368 patients were randomized to receive a urinary FSH (uFSH) bolus (6 ampules, 450 IU) and placebo, respectively, at the time of the hCG trigger. The primary outcome measure was clinical pregnancy rate. The secondary outcome measures were FSH level on the day of oocyte retrieval, number of oocytes retrieved, good-quality embryo rate, live birth rate and rate of OHSS. MAIN RESULTS AND THE ROLE OF CHANCE There were no significant differences in the baseline demographic characteristics between the two study groups. There were also no significant differences between groups in cycle characteristics, such as the mean number of stimulation days, total gonadotrophin dose and peak estradiol. The clinical pregnancy rate was 51.6% in the placebo group and 52.7% in the FSH co-trigger group, with an absolute rate difference of 1.1% (95% CI −6.1% to 8.3%). The number of oocytes retrieved was 10.47 ± 4.52 and 10.74 ± 5.01 (P = 0.44), the rate of good-quality embryos was 37% and 33.9% (P = 0.093) and the implantation rate was 35% and 36% (P = 0.7) in the placebo group and the FSH co-trigger group, respectively. LIMITATIONS, REASONS FOR CAUTION This was a single-center study, which may limit its effectiveness. The use of uFSH is a limitation, as this is not the same as the natural FSH. We did not collect follicular fluid for further study of molecular changes after the use of uFSH as a co-trigger. WIDER IMPLICATIONS OF THE FINDINGS Based on previous data and our results, an additional FSH bolus administered at the time of hCG trigger has no benefit on clinical pregnancy rates in women undergoing the long GnRHa protocol in IVF/ICSI: a single hCG trigger is sufficient. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the National Key Research and Development Program of China (2016YFC1000205); Sun Yat-Sen University Clinical Research 5010 Program (2016004); the Science and Technology Project of Guangdong Province (2016A020216011 and 2017A020213028); and Science Technology Research Project of Guangdong Province (S2011010004662). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER The trial was registered in the Chinese Clinical Trial Registry (ChiCTR-TRC-12002246). TRIAL REGISTRATION DATE 20 May 2012. DATE OF FIRST PATIENT’S ENROLMENT 10 June 2012.

Background Preclinical studies indicate iron deficiency (ID) plays an important role in cardiac remodelling. However, the relationship between ID and cardiac remodelling remains unknown in clinical setting. This retrospective study aims to identify a potential biomarker for the myocardial remodelling in patients with ID. Due to limited patients with ID are identified without iron deficiency anaemia (IDA), we analyse the relationship of total iron binding capacity (TIBC) and the left ventricular mass index (LVMI) in patients with iron deficiency anaemia. Methods A total of 82 patients with IDA exhibiting the diagnostic criteria for IDA were enrolled in the study. Among the patients, 65 had reported LVMI values. Subsequently, these patients were divided into two groups according to abnormal LVMI (> 115 g/m2 in men and > 95 g/m2 in women). Linear bivariate analysis was performed to detect the associations of haemoglobin or TIBC with clinical and echocardiographic characteristics. Simple linear regression analysis was used to evaluate the correlation between LVMI and the parameters of IDA, while multivariable linear analysis was used to assess the association of LVMI with age, TIBC and haemoglobin. Logistic regression analysis was utilized to determine the relationship of LV remodelling with anaemia severity and TIBC. Results As compared with control group, the levels of TIBC in abnormal LVMI group are increased. Using log transformed LVMI as the dependent variable, simultaneously introducing age, TIBC, and haemoglobin into the simple linear regression or multivariable linear regression analysis confirmed the positive association among these factors. Bivariate correlation analysis reveals the irrelevance between haemoglobin and TIBC. In logistic regression analysis, TIBC is associated with the risk of LV remodelling. Conclusions Results of study indicate that TIBC exhibit an explicit association with LVMI in patients with iron deficiency anaemia. Logistic analysis further confirms the contribution of TIBC to abnormal LVMI incidence among this population with IDA.

While wound therapy remains a clinical challenge in current medical practice, much effort has focused on developing biological therapeutic approaches. This paper presents a comprehensive review of delivery systems for current biologicals for the treatment of chronic wounds and severe burns. The biologicals discussed here include proteins such as growth factors and gene modifying molecules, which may be delivered to wounds free, encapsulated, or released from living systems (cells, skin grafts or skin equivalents) or biomaterials. Advances in biomaterial science and technologies have enabled the synthesis of delivery systems such as scaffolds, hydrogels and nanoparticles, designed to not only allow spatially and temporally controlled release of biologicals, but to also emulate the natural extracellular matrix microenvironment. These technologies represent an attractive field for regenerative wound therapy, by offering more personalised and effective treatments.

Alcoholic liver disease (ALD) includes a spectrum of hepatic abnormalities that range from isolated alcoholic steatosis to steatohepatitis and cirrhosis. Naringenin, a predominant flavanone in grapefruit, increases resistance to oxidative stress and inflammation and protects against multiple organ injury in various animal models. However, the specific mechanisms responsible for protection against alcoholic injury are poorly understood. In the present study, we aimed to investigate the effect of naringenin on alcoholic events and the molecular regulatory mechanisms of naringenin in the liver and whole body of zebrafish larvae following exposure to 350 mmol/l ethanol for 32 h. Zebrafish larvae {4 days post‑fertilization (dpf); wild-type (WT) and a transgenic line with liver-specific eGFP expression [Tg(lfabp10α-eGFP)]} were used to establish an alcoholic fatty liver model in order to evaluate the effects of naringenin treatment on anti-alcoholic injury. Naringenin significantly reduced alcoholic liver morphological phenotypes and the expression of alcohol and lipid metabolism-related genes, including cyp2y3, cyp3a65, hmgcra, hmgcrb, fasn, fabp10α, fads2 and echs1, in zebrafish larvae. Naringenin also attenuated hepatic apoptosis in larvae as detected by TUNEL staining, consistent with the expression of critical biomarkers of endoplasmic reticulum stress and of DNA damage genes (chop, gadd45αa and edem1). The present study showed that naringenin inhibited alcohol-induced liver steatosis and injury in zebrafish larvae by reducing apoptosis and DNA damage and by harmonizing alcohol and lipid metabolism.

Glucagon has plenty of effects via a specific glucagon receptor(GCGR) like elevating the blood glucose, improving fatty acids metabolism, energy expenditure and increasing lipolysis in adipose tissue. The most important role of glucagon is to regulate the blood glucose, but the emergent possibilities of hyperglycaemia is exist. Glucagon could also slightly activate glucagon-like peptide-1 receptor(GLP-1R), which lead to blood glucose lowering effect. This study aims to erase the likelihood of hyperglycaemia and to remain the inherent catabolic effects through improving GLP-1R activation and deteriorating GCGR activation so as to lower the bodyweight and show diabetes-protective effects. Firstly, twelve cysteine modified GLP-1/GCGR dual agonists were synthesized (1–12). Then, the GLP-1R/GCGR mediated activation and biological activity in normal ICR mice were comprehensively performed. Compounds substituted by cysteine at positions 22, 23 and 25 in glucagon were observed to be better regulators of the body weight and blood glucose. To prolong the half-lives of derivatives, various fatty side chain maleimides were modified to optimal glucagon analogues. Laurate maleimide conjugate 4d was the most potent. Administration of 1000 nmol/kg 4d once every two days for a month normalized adiposity and glucose tolerance in diet-induced obese (DIO) mice. Improvements in plasma metabolic parameters including insulin, leptin, and adiponectin were observed. These studies suggest that compound 4d behaves well in lowering body weight and maintaining energy expenditure without a chance of hyperglycaemia, 4d has strong clinical potential as an efficient GLP-1/GCGR agonist in the prevention and treatment of obesity and dyslipidemia.

Compared with traditional anti-tumor drugs, antimicrobial peptides as novel anti-tumor agents have prominent advantages of higher specificity and circumvention of multi-drug resistance. BP100 is a multifunctional membrane-active peptide with high antimicrobial activity. Taking BP100 as a lead peptide, we designed and synthesized a series of aliphatic chain-conjugated peptides through solid-phase synthesis. Biological evaluation revealed that these peptides exhibited better anti-cancer activity than BP100. Further investigations revealed that these peptides could disrupt the cell membrane and trigger the cytochrome C release into cytoplasm, which ultimately resulted in apoptosis. Meanwhile, these peptides also exhibited effective anti-tumor activity against multidrug resistant cells and had multidrug resistance-reversing effect. Additionally, conjugation of aliphatic acid to those peptides could enhance their stability in plasma. In conclusion, aliphatic acid-modified peptides might be promising anti-tumor agents for cancer therapy.

Host defense peptides have been demonstrated to exhibit prominent advantages in cancer therapy with selective binding ability toward tumor cells via electrostatic attractions, which can overcome the limitations of traditional chemotherapy drugs, such as toxicity on non-malignant cells and the emergence of drug resistance. In this work, we redesigned and constructed a series of cationic peptides by inserting hydrophobic residues into hydrophilic surface or replacing lysine (K) with arginine (R), based on the experience from the preliminary work of host defense peptide B1. In-depth studies demonstrated that the engineered peptides exhibited more potent anti-cancer activity against various cancer cell lines and much lower toxicity to normal cells compared with B1. Further investigation revealed that compounds I-3 and I-7 could act on cancer cell membranes and subsequently alter the permeability, which facilitated obvious pro-apoptotic activity in paclitaxel-resistant cell line (MCF-7/Taxol). The result of mitochondrial membrane potential assay (ΔΨm) demonstrated that the peptides induced ΔΨm dissipation and mitochondrial depolarization. The caspase-3 cellular activity assay showed that the anti-cancer activity of peptides functioned via caspase-3-dependent apoptosis. The study yielded compound I-7 with superior properties for antineoplastic activity in comparison to B1, which makes it a promising potential candidate for cancer therapy.

A novel mitochondria-targeting fluorescent probe compound S-N3 for hydrogen sulfide (H2S) in living cells has been designed and synthesized in this study. This article contained the chemosynthesis and some studies on bioactivity of the target compound in living cells. Compound S-N3 is easy to synthesize and can remain stable under the effect of pH, system and photostability. In addition, it shows low cytotoxicity in cell imaging. And it can react with H2S highly selective in PBS or FBS solution, which would cause the obvious increase in fluorescence intensity. Therefore, the low-cost detection method for H2S is allowed for monitoring the quantity of H2S existed in the mitochondria.

De novo lipogenesis is tightly regulated by insulin and nutritional signals to maintain metabolic homeostasis. Excessive lipogenesis induces lipotoxicity, leading to nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. Genetic lipogenic programs have been extensively investigated, but epigenetic regulation of lipogenesis is poorly understood. Here, we identified Slug as an important epigenetic regulator of lipogenesis. Hepatic Slug levels were markedly upregulated in mice by either feeding or insulin treatment. In primary hepatocytes, insulin stimulation increased Slug expression, stability, and interactions with epigenetic enzyme lysine-specific demethylase-1 (Lsd1). Slug bound to the fatty acid synthase (Fasn) promoter where Slug-associated Lsd1 catalyzed H3K9 demethylation, thereby stimulating Fasn expression and lipogenesis. Ablation of Slug blunted insulin-stimulated lipogenesis. Conversely, overexpression of Slug, but not a Lsd1 binding-defective Slug mutant, stimulated Fasn expression and lipogenesis. Lsd1 inhibitor treatment also blocked Slug-stimulated lipogenesis. Remarkably, hepatocyte-specific deletion of Slug inhibited the hepatic lipogenic program and protected against obesity-associated NAFLD, insulin resistance, and glucose intolerance in mice. Conversely, liver-restricted overexpression of Slug, but not the Lsd1 binding-defective Slug mutant, had the opposite effects. These results unveil an insulin/Slug/Lsd1/H3K9 demethylation lipogenic pathway that promotes NAFLD and type 2 diabetes.

Muscle-related disorders, such as sarcopenia and cachexia, caused by aging and chronic diseases can lead to the loss of muscle mass and strength to different degrees, severely affecting human health. Globally, tea is one of the three most popular beverages, and its major active ingredient catechins have been reported to delay muscular atrophy and enhance movement. However, currently, there is no systematic review to elaborate its roles and the associated mechanisms. This article reviews the (1) functions and mechanisms of catechins in the differentiation of myogenic stem cells, biogenesis of mitochondria, synthesis and degradation of proteins, regulation of glucose level, and metabolism of lipids in muscle cells; and (2) effect of catechins on the blood vessels, bones, and nerves that are closely related to the skeletal muscles. Catechins could prevent, mitigate, delay, and even treat muscle-related disorders caused by aging and diseases.

Background:A recent patent has been issued for hydroxysafflor yellow A (HSYA) as a drug to prevent blood circulation disorders. Hydroxysafflor yellow B (HSYB), an isomer of HSYA with antioxidative effects, has been isolated from the florets of Carthamus tinctorius. The effects of HSYB on the proliferation of cancer cells and its mechanism of action have not been investigated.Objective:The aims of this study were to investigate the anti-cancer effects and the molecular mechanism of HSYB for breast cancer MCF-7 cells.Methods:MTT assays and colony formation assays were used to assess the survival and proliferation of MCF-7 cells, respectively. Hoechst 33258 and flow cytometry were used to measure cell apoptosis and flow cytometry to determine effects on the cell cycle. Western blots were used to measure protein levels.Results:Treatment with HSYB reduced survival and proliferation of human breast cancer MCF-7 cells in a dose-dependent manner. Furthermore, HSYB arrested the MCF-7 cell cycle at the S phase and downregulated cyclin D1, cyclin E, and CDK2. Compared with a control group, HSYB suppressed the protein levels of p-PI3K, PI3K, AKT, and p-AKT in MCF-7 cells. In addition, HSYB decreased the levels of Bcl- 2, increased the levels of Bax, cleaved caspase-3 and caspase-9, and subsequently induced MCF-7 cell apoptosis.Conclusion:These data demonstrate that HSYB arrests the MCF-7 cell cycle at the S phase and induces cell apoptosis. Patent US20170246228 indicates that HSYB can be potentially used for the prevention and treatment of human breast cancer.

ObjectiveThe objective of this retrospective cohort study was to explore the optimal range of the total progressive motile sperm count (TPMSC) for live birth in couples with varying infertility diagnosis undergoing intrauterine insemination (IUI) in a university-affiliated teaching hospital.MethodsA total of 2647 couples and 5171 IUI cycles were included between January 2015 and December 2018. Of those, 1542 cycles were performed due to unexplained infertility, 1228 cycles due to anovulation, 1120 cycles due to mild male factor infertility and 122 cycles due to mild endometriosis. The primary outcome measure was live birth rate (LBR). The secondary outcome measure was clinical pregnancy rate (CPR).ResultsThe CPR and LBR were highest in patients with a diagnosis of anovulation compared with the other three groups of patients. The CPR and LBR in patients with unexplained, mild male factor and mild endometriosis were comparable. For the patients with mild male factor infertility, the CPR with prewash TPMSC of >75.0 M and postwash TPMSC of 65.10 M was above 10%, statistically significantly higher than other quartiles of TPMSC (p65.10 M was statistically significantly higher than other groups (p40 years of age.ConclusionsIn conclusion, the infertility diagnosis plays a significant role for the patient undergoing IUI. Thus, the anovulatory patients benefitted most from IUI, irrespective of TPMSC. For patients with unexplained infertility, TPMSC does not affect the success rate of IUI. Overall,female patients more than 40 years old should not be referred to IUI.

Background The rules and mechanisms of seasonal changes in plasma lipid levels, which may be related to annual rhythmicity of incidence and mortality of cardiovascular diseases, are still controversial. Objective The objectives of this study were to study the effects of climatic factors on plasma lipid levels and to preliminarily reveal mechanisms of annual rhythmicity of plasma lipid levels. Methods A longitudinal study was performed using health examination data of 5 consecutive years (47,270 subjects) in Jinan, China. The climate in Jinan is typical temperate continental monsoon climate with huge temperature difference between winter and summer (>30°C). Results After considering and adjusting those classical lipid-associated risk factors, such as age, gender, diet, exercise, blood pressure, body weight, change of body weight, body mass index, glycemia, alanine aminotransferase, and creatinine, only air temperature could still significantly affect plasma lipid levels among the main climatic factors (humidity, precipitation, and so forth). For men, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol was decreased significantly 0.35, 0.18, and 0.06 mmol/L, respectively, whereas triglyceride was increased significantly 0.12 mmol/L for every 10°C increase in air temperature. For women, total cholesterol and high-density lipoprotein cholesterol were decreased notably 0.73 and 0.32 mmol/L, and low-density lipoprotein cholesterol was increased significantly 0.26 mmol/L for every 10°C increase in air temperature, whereas triglyceride was not significantly affected by air temperature. Conclusion Air temperature is an independent risk factor for plasma lipid levels besides those classical lipid-associated risk factors. The annual air temperature fluctuations might be an important mechanism of the seasonal changes of lipids.

Epigallocatechin-3-gallate (EGCG) is a secondary metabolite in green tea, which has various physiological activities, including antioxidant, antitumor, and antiviral activities. Studies have shown that EGCG has a preventive effect on infertility by protecting germ cells and oocytes from damage. EGCG functions mainly through the regulation of ROS (reactive oxygen species) levels, which affect the expression of catalase (CAT), superoxide dismutase 1(SOD1), superoxide dismutase 2(SOD2), and glutathione peroxidase (GPx), has positive influence on other enzyme activities in germ cells and oocytes, and actively alters antioxidant activities. These enzymes above can inhibit the activation of extracellular signal-regulated proteins (Erk), induce apoptosis, and control the production of ROS in tissue cells. Here, we present a comprehensive overview of the mechanisms underlying the main physiological activities of EGCG, including antioxidant, antitumor, and antiviral activities, and their potential roles in male and female reproductive systems and fertility. This paper discusses the mechanisms by which EGCG retards the infertility of germ cells and oocytes and provides a supportive recommendation for improving fertility in humans and animals. We hope it will provide useful references for related research in mammalian reproduction.

Dark tea is a unique fermented tea produced by solid-state fermentation of tea leaves (Camellia sinensis). It includes ripe Pu-erh tea, Fu brick tea, Liupao tea, and other teas. Microbial fermentation is considered to be the key factor controlling the quality of dark tea. It involves a series of reactions that modify the chemical constituents of tea leaves. These chemical conversions during microbial fermentation of dark tea are associated with a variety of functional core microorganisms. Further, Multi-omics approaches have been used to reveal the microbial impact on the conversion of the chemical components in dark tea. In the present review, we provide an overview of the most recent advances in the knowledge of the microbial bioconversion of the chemical components in dark tea, including the chemical composition of dark tea, microbial community composition and dynamics during the fermentation process, and the role of microorganisms in biotransformation of chemical constituents.

Current magnetic resonance imaging (MRI)-guided pH-switching therapeutic platforms have encountered problems such as low relaxation rates, poor pH-switching efficiencies, and a lag in the drug release behind the MRI. Herein, we designed a nanoplatform with tunable pore size, which could match the size of drug molecules for pH-switching MRI and chemotherapy via ultrasmall manganese oxide-capped mesoporous silica nanoparticles (USMO@MSNs). USMO@MSN could quickly dissolve under weakly acidic conditions and leach abundant Mn2+ ions (leaching ratio: 76%), enhancing the MR contrast. The longitudinal relaxation rate (r1) of USMO@MSNs significantly increased from 0.65 to 5.61 mM–1 s–1 as the pH decreased from 7.4 to 4.5, showing an ultrahigh-efficiency pH-switching T1-weighted MR contrast ability for in vivo tumor. Meanwhile, the matching pore structure allowed effective loading of doxorubicin (DOX) on USMO@MSNs to form smart therapeutic system (USMO@MSNs-DOX). The DOX release rate was strongly proportional to th...

OBJECTIVE: To screen differentially expressed lncRNAs involved in OHSS. OHSS is defined as ovarian hyperstimulation syndrome. It is characterized as enlarged ovary and increased vascular permeability. DESIGN: Case-control study. SETTING: University-affiliated hospital. PATIENT(S): Patients with OHSS high risk (n = 30) and low risk (n = 30) were included in this study. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): LncRNAs from women with OHSS high risk and low risk were used for high-throughput sequencing profiling. The eight most differentially expressed lncRNAs in granulosa cells were validated by semi-quantitative reverse transcription-polymerase chain reaction analysis. RESULT(S): A total of 23,815 lncRNAs were detected and 482 were differentially expressed (fold-change ≥2; p

Polycystic ovary syndrome (PCOS) is a common endocrine disease that affects reproductive-aged women and mostly characterized by insulin resistance (IR). The underlying mechanism remains unknown. Long noncoding RNAs (lncRNAs) have been demonstrated to be involved in various levels of biological regulation process of cell development, metabolism, and differentiation. This study aims to investigate the relationship between IR and differential expression of lncRNA Growth-arrest specific transcript 5 (GAS5) in patients' serum with and without PCOS. A total of 76 cases of serum was collected from non-PCOS and PCOS patients with and without IR to measure interleukin-18 (IL-18) and GAS5 expression, which were correlated with IR status. The IL-18 concentration in serums was significantly increased in PCOS patients with IR. GAS5 expression was decreased in serums in PCOS patients with IR. Result of correlation analysis shows that there is a negative association between GAS5 expression and homeostasis model of assessment for insulin resistance (HOMA-IR). GAS5 was yielded the ROC curve (AUC). Our study implied that elevated IL-18 expression and downregulation of GAS5 in serums might contribute to IR in PCOS patients.

To observe the effects of Alpha-lipoic acid (ALA) on oxidative stress (OS) in vivo and urinary podocalyxin (PCX, the glomerular podocyte marker protein) excretion in type 2 diabetics and explore its possible protective mechanisms on glomerular podocytes.Thirty-six type 2 diabetics were recruited as observation group and treated with ALA on the basis of initial therapy for six months, and 30 healthy subjects were selected as control group. FBG, HbA1c, serum glutathione peroxidase (SGSH-Px), superoxide dismutase (SSOD) activity, urinary malondialdehyde (UMDA), 8-hydroxy-deoxyguanosine (U8-OHdG), albumin (UALB), creatinine (UCr) and urinary PCX (UPCX) were determined at baseline and after six months' observation.Compared with the control group, the ratios of UMDA/UCr (UMCR), U8-OHdG/UCr (U8CR), UALB/UCr (UACR) and UPCX/UCr (UPCR) increased markedly, SGSH-Px and SSOD decreased significantly in the diabetics (P0.01); after sixth month treatment, the levels of UMCR, U8CR, UACR and UPCR reduced and SGSH-Px and SSOD increased markedly in the observation group (P0.05) with no significant changes in FBG and HbA1c. UPCR had positive correlation with UACR, UMCR and U8CR (r=0.720, r=0.661, r=0.698, P0.01), and negative correlation with SGSH-Px and SSOD in the diabetics (r=-0.608, r=-0.559, P0.01).ALA can provide some protection against glomerular podocyte injury in type 2 diabetics, which may be related partly to its effects in alleviating enhanced OS and strengthening antioxidant ability in vivo.

Studies on the relationship between thyroid function and non-alcoholic fatty liver disease (NAFLD) among euthyroid subjects have produced conflicting results.The aim of this study was to investigate the association between thyroid function and the presence of NAFLD in a large-sample middle-aged euthyroid subjects.A total of 2576 euthyroid subjects who underwent health check-up were included. NAFLD was diagnosed by hepatic ultrasonography. Conventional risk factors for NAFLD were assessed as well as serum levels of TSH, FT3 and FT4.Levels of FT3 were significantly higher in NAFLD group (5.12 ± 0.58 versus 4.84 ± 0.58 pmol/L, adjusted p = 0.000) than non-NAFLD group, while levels of TSH and FT4 were comparable between NAFLD and non-NAFLD groups (TSH: 2.13 ± 0.90 versus 2.20 ± 0.93 mIU/L, adjusted p = 0.190; FT4: 16.41 ± 2.04 versus 16.18 ± 2.06 pmol/L, adjusted p = 0.146, respectively). Levels of FT3 were positively correlated with components of metabolic syndrome. Multivariate logistic regression analysis revealed that high level of FT3 was an independent predictor for NAFLD (odds ratio: 1.253, p = 0.040). The relationship between FT4 and NAFLD in women was different according to menopausal status, with negative association in pre-menopausal women (OR: 0.777, 95% CI: 0.617-0.979, p = 0.032) and null association in post-menopausal women (OR: 1.037, 95% CI: 0.841-1.277, p = 0.736).Our findings suggested that high levels of FT3 were significantly associated with NAFLD among middle-aged euthyroid subjects independently of known metabolic risk factors. A negative correlation of serum FT4 level with NAFLD was only observed in pre-menopausal women.

In this study, we report that daily administration of luteolin for 8 weeks improved hepatic steatosis by repressing hepatic TG accumulation and increasing glycogen storage. Luteolin inhibited hepatic de novo lipid synthesis by regulating the LXR-SREBP-1c signaling pathway, which is over-activated in the livers of db/db mice. Further in vitro studies revealed that luteolin can competitively bind to the ligand binding domain to suppress the LXR activation induced by an LXR agonist and high glucose, thereby decreasing TG accumulation in HepG2 cells and primary hepatocytes. Taken together, our results indicate that luteolin can abolish lipid accumulation induced by LXR-SREBP-1c activation both in vivo and in vitro, and may have potential as a therapeutic agent for treating NAFLD.

// Weichao Zhong 1, 2, * , Lei Gao 1, * , Zhenting Zhou 1 , Haiyan Lin 1 , Chun Chen 3 , Peng Huang 1 , Weiliang Huang 1 , Chuying Zhou 1 , Shaohui Huang 1 , Linghui Nie 1 , Ye Liu 4 , Youming Chen 4 , Daqiao Zhou 2 and Zhiping Lv 1 1 School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China 2 Department of Liver Diseases, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, 518033, China 3 Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, 515041, China 4 The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, 510630, China * These authors contributed equally to this work Correspondence to: Zhiping Lv, email: lzp48241@126.com Daqiao Zhou, email: zdqdoctor@sina.com Keywords: indoleamine 2,3-dioxygenase 1, liver fibrosis, T helper 17 cells, tryptophan 2,3-dioxygenase, 1-methyl-D-tryptophan Received: November 04, 2016 Accepted: April 03, 2017 Published: April 15, 2017 ABSTRACT Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular rate-limiting enzyme in the metabolism of tryptophan along the kynurenine pathway, subsequently mediating the immune response; however, the role of IDO1 in liver fibrosis and cirrhosis is still unclear. In this study, we investigated the role of IDO1 in the development of hepatic fibrosis and cirrhosis. Patients with hepatitis B virus-induced cirrhosis and healthy volunteers were enrolled. For animals, carbon tetrachloride (CCl 4 ) was used to establish liver fibrosis in wild-type and IDO1 knockout mice. Additionally, an IDO1 inhibitor (1-methyl- D -tryptophan) was administered to WT fibrosis mice. Liver lesions were positively correlated with serum IDO1 levels in both the clinical subjects and hepatic fibrosis mice. A positive correlation between serum IDO1 levels and liver stiffness values was found in the cirrhosis patients. Notably, IDO1 knockout mice were protected from CCl 4 -induced liver fibrosis, as reflected by unchanged serum alanine transaminase and aspartate transaminase levels and lower collagen deposition, α-smooth muscle actin expression and apoptotic cell death rates. On the other hand, tryptophan 2,3-dioxygenase (TDO), another systemic tryptophan metabolism enzyme, exhibited a compensatory increase as a result of IDO1 deficiency. Moreover, hepatic interleukin-17a, a characteristic cytokine of T helper 17 (Th17) cells, and downstream cytokines’ mRNA levels showed lower expression in the IDO1 –/– model mice. IDO1 appears to be a potential hallmark of liver lesions, and its deficiency protects mice from CCl 4 -induced fibrosis mediated by Th17 cells down-regulation and TDO compensation.

To evaluate whether delayed initiation of gonadotropin in luteal long protocol affected the outcome of in vitro fertilization (IVF).Prospective randomized study at the reproductive centre of a university-based hospital. Eighty-five subfertile women undergoing IVF embryo transfer after a standardized gonadotropin-releasing hormone agonists (GnRHa) long protocol. The patients were randomized into group A (stimulated 3 weeks after GnRHa administration) and group B (stimulated 2 weeks after GnRHa administration), according to the time of gonadotropin initiation after GnRHa-mediated pituitary suppression. The main outcome measures were clinical pregnancy and live birth rates.There were no significant differences in baseline characteristics such as age, body mass index and basal follicle-stimulating hormone (bFSH) between the two groups. In group B, the days of gonadotropin stimulation were significantly greater than that in group A (p 0.05), while the total dose of gonadotropin in group A was comparable to that in group B. Serum luteinizing hormone was lower and follicle-stimulating hormone higher in group A than in group B (p 0.05) on initiation day. There were no significant differences in hormone profile measurements between the two groups. Moreover, the clinical pregnancy rate, implantation rate, live birth rate, miscarriage rate and moderate ovarian hyperstimulation syndrome rate were not significantly different between the groups.Delay of gonadotropin stimulation in a standard long protocol may increase clinical efficiency, without significantly changing clinical outcome.

Angiogenesis is an important mechanism that protects tissue against necrosis following acute ischemic injury. The aim of this study was to investigate whether the Toll-like receptor 2 (TLR2) signaling pathway is involved in angiogenesis following ischemic injury by cell migration and lymphocyte invasion assays in vitro, and a mouse model of hindlimb ischemia by ligation in vivo, respectively. To assess the potential role of TLR2 activation in endothelial cell permeability, HUVECs were pretreated with Pam3CSK4 and analyzed using wound repair and transwell assays. The results showed that the TLR2 agonist induced human umbilical vein endothelial cell (HUVEC) migration and increased the permeability of HUVECs to lymphocyte. The lymphocyte invasion of TLR2 knockout (TLR2-/-) mice was inhibited as compared to that of wild-type (WT) mice. In the mouse model of hindlimb ischemia by ligation, blood perfusion of operated limbs was significantly lower in TLR2-/- compared to WT mice, 7 and 14 days after ligation. TLR2-/- mice showed a decreased CD31 expression in ischemic gastrocnemius at 7 and 14 days after ligation, reduced interleukin-6 (IL-6) level and lowered tumor necrosis factor-α (TNF-α) levels. These findings demonstrated that TLR2 activation promotes cell migration, cell permeability and the lymphocyte invasion of endothelial cells. TLR2 activation promotes angiogenesis in vivo, which may be associated with the serum of TNF-α levels and IL-6 release.

Background Dark skin has different properties in comparison to fair skin. Melanocytes have been shown to partly contribute to these differences, however, the involvement of keratinocytes from dark or fair skin is not well demonstrated. Objectives This study investigated the proliferation and barrier function of dark keratinocytes (DK) and fair keratinocytes (FK), and the role of protease activated receptor (PAR)1 and PAR2. Methods DK and FK were isolated from human neonatal foreskins. Cells were treated with PAR1/PAR2 agonists or antagonists, proliferation was measured by BrdU assay; permeability by the flux of FITC-dextran; protein expression by immunostaining or western blot. Results When compared to FK, DK proliferated significantly slower; had higher cell permeability; expressed less phosphorylated (P)-ERK/ERK, caspase-14, E-cadherin, tissue growth factor (TGF)-β3 and PAR1; and expressed more PAR2, and matrix metalloproteinase (MMP)-9. Activation of PAR1 or inhibition of PAR2 stimulated cell proliferation and ERK activation, and in concordance inhibition of PAR1 or activation of PAR2 suppressed cell proliferation and ERK activation in both DK and FK. Inhibition of PAR2 decreased and inhibition of PAR1 increased cell permeability. In foreskin sections, the epidermis of dark foreskin expressed less caspase-14 and the same level but different distribution of E-cadherin, when compared to fair foreskin. Conclusions These data highlight functional differences in proliferation and barrier integrity between HK and FK that are partly associated with their differential expression of PAR1 and PAR2.

Dyslipidemia in thyroid dysfunction has always been attributed to changes in thyroid hormone (TH) levels. We hypothesized that TSH plays an important role in lipid metabolism independent of TH.We conducted a cross-sectional study to investigate the relationship between serum TSH levels and lipid profiles after controlling for free T(3), free T(4), total T(3), total T(4) and nonthyroid factors relevant to lipid metabolism in euthyroid Chinese subjects.General linear analysis was performed to determine whether the impact of TSH on serum lipid levels is independent of the TH levels. Moreover, path analysis, an evolutionary multivariable regression technique, was conducted to test whether there is a direct and/or indirect effect between serum TSH and total cholesterol (TC) levels. Additionally, the odds ratios (95% confidence interval) for hypercholesterolemia in relation to TSH categories were calculated.A total of 3664 euthyroid subjects were finally analyzed. There was a significant linear trend toward higher log TC (P = 0.021) and log triglyceride (P = 0.001) levels with increasing serum TSH levels within the reference range, which remained significant after adjusting for factors such as TH levels, age, and smoking. Most importantly, the total effect of TSH on TC levels (total effect(TC, TSH) = 0.05253) includes a direct effect (direct effect(TC, TSH) = 0.05979) and an indirect effect via TH. Compared with subjects in the lower part of the reference range (TSH level, 0.27-0.61 mIU/liter), the adjusted odds ratio for hypercholesterolemia was 3.239 (95% confidence interval, 1.392-7.538; P = 0.007) for those in the upper category (TSH level, 4.61-5.5 mIU/liter).The variation in normal TSH levels is partially related to the lipid components and hypercholesterolemia in euthyroid subjects and includes both TH-dependent and TH-independent effects. Our study suggests the importance of controlling TSH in hypothyroid subjects.

A series of capsaicin derivatives were designed and synthesized, including 10 compounds which are the combination of capsaicin and dihydro capsaicin with ibuprofen through bridge chain. Preliminary biological tests suggested that some compounds had both anti-inflammatory activity and analgesic activity. And their pungency was lower. Based on these results, some of these molecules can be considered as lead candidates for the further development of analgesic drugs.

High expression of the epidermal growth factor receptor (EGFR) has been implicated in the development of pancreatic cancer. Gefitinib is an orally active and selective EGFR-TKI (EGFR-tyrosine kinase inhibitor) that blocks signal transduction pathways responsible for the proliferation and survival of cancer cells, and other host-dependent processes promoting cancer growth. This study investigated the anticancer effect of gefitinib on human pancreatic cancer cells and the molecular mechanism involved. We first evaluated the effect of gefitinib on cell proliferation with MTT assay and the results demonstrated that gefitinib significantly inhibited the proliferation of pancreatic cancer cells. Flow cytometric analysis showed that gefitinib induced a delay in cell cycle progression and a G0/G1 arrest together with a G2/M block; these were associated with increased expression of p27(Kip1) cyclin-dependent kinase inhibitor combined with decreased expression of aurora B. Besides, luciferase reporter assay revealed that transcriptional mechanism was responsible for the down-regulation of aurora B protein by gefitinib. Overall, the results suggest a mechanistic connection among these events to provide new insights into the mechanism underlying the antiproliferative effect of gefitinib on pancreatic cancer and supplement a theory basis of gefitinib in clinical treatment of pancreatic cancer.

A retrospective study conducted in an academic reproductive medicine centre evaluated the feasibility and safety of early fetal reduction in dichorionic triplets to dichorionic twin or singleton pregnancies. Thirty-three dichorionic triplets that underwent early transvaginal fetal reduction mechanically between 2002 and 2013 were included, of which 21 patients underwent fetal reduction to dichorionic twins (Group A) and 12 patients underwent fetal reduction to a singleton pregnancy (Group B). A further 84 patients with trichorionic triplets reduced to twins were included as the control group (Group C). The main outcome measures were live birth and preterm labour rates. Both early and late spontaneous abortion rates, were similar in group A compared with groups B and C. Gestational age at delivery was significantly lower in group C versus group A (P = 0.02). The preterm labour rate in group A, which was comparable with that in group C, was greater than in group B, but not significantly. Neonatal birth weight, low birth weight rate and neonatal body height were similar among groups. Small for gestational age rates were comparable. Live birth rates were similar among the groups. Early transvaginal fetal reduction for dichorionic triplets to dichorionic twins may be feasible and safe.

Objectives To explore the longitudinal effect of metabolic syndrome (MetS) and its components on the development of non-alcoholic fatty liver disease (NAFLD) and to evaluate the significance of MetS and its components as early markers of NAFLD risk in a northern urban Han Chinese population. Materials and methods A total of 15,791 cohort members without NAFLD at baseline were included in the current study between 2005 and 2011. The baseline characteristics of the cohort were compared by MetS status at baseline and NAFLD status after follow-up. Cox proportional hazards models were used to estimate the unadjusted or adjusted hazard ratios (HRs) for development of NAFLD among individuals with MetS compared with individuals without MetS at baseline. Results During 51,652 person-years of follow-up, 3913 (24.78%) new cases of NAFLD occurred between 2005 and 2011. In the unadjusted model, the HR (95% confidence interval [CI]) for NAFLD was 2.51 (2.30, 2.73). After adjusting for gender, age, diet, smoking status, and regular exercise, the HR was 1.94 (1.78, 2.13). Gender differences were observed, with adjusted HRs (95% CIs) of 1.89 (1.71, 2.09) and 1.72 (1.43, 2.07) among males and females, respectively. Compared with individuals without MetS components, the HRs were 1.92 (1.76, 2.09), 2.64 (2.40, 2.90) and 3.51 (3.15, 3.91) for individuals with one, two, or three or more MetS components, respectively. Moreover, participants with obesity or hyperlipidemia had a higher risk of NAFLD than patients with hypertension or hyperglycemia, with HRs of 2.03 (1.83, 2.25) for obesity, 1.94 (1.72, 2.19) for hyperlipidemia, and 3.01 (2.68, 3.37) for these factors in combination. Conclusion The present study indicates that MetS and its components independently predict the risk of NAFLD in a northern urban Han Chinese population and suggests that people with MetS or its component should initiate lifestyle changes to prevent the development of NAFLD.

Background: Concomitant occurrence of invasive pulmonary aspergillosis (IPA) with cryptogenic organizing pneumonia (COP) is scarce. Here, we report a case where COP was a presenting feature in a patient with diagnosed IPA, and review additional 58 COP patients reported in the literature from 1988 through 2013. Case outline: The study was reviewed and approved by the Institutional Ethics Committee of Shanghai Tenth People’s Hospital of Tongji University and was conducted in compliance with the Helsinki Declaration. Written informed consent was obtained from patient. A 56-year-old man presenting with productive cough for several weeks and unremitting high fever for a week was hospitalized with an initial clinical diagnosis of pneumonia, for which antibiotics were prescribed but did not work. Seeing that the condition progressed both clinically and radiographically, bronchoscopy, bronchoalveolar lavage and lung biopsy were performed, and the diagnosis of cryptogenic organizing pneumonia (COP) and invasive pulmonary aspergillosis (IPA) co-existence was made. Initially, the patient responded to steroid pulse therapy and voriconazole treatment, and his condition was partially improved. However, the patient’s condition deteriorated progressively 5 months after the disease onset and the patient died during the third admission due to respiratory failure and the adverse reactions of coriaceous hormone therapy. Conclusion: The diagnosis of cryptogenic organizing pneumonia (COP) and invasive pulmonary aspergillosis (IPA) co-occurrence depends on clinical, radiological and histological presentations. Similarities with other disease processes could lead to a delayed diagnosis or misdiagnosis. The present case suggests that clinicians should be alert to this disease in their clinical practices.