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BACKGROUND: Psoriasis is a chronic inflammatory skin disease characterized by a complex pathogenesis involving various types of cells and cytokines. Among those, the pro-inflammatory cytokine IL-23/IL-17A axis plays a crucial role in the development and rapid progression of psoriasis. Phenformin, a derivative of metformin and a member of the biguanide class of drugs, exhibits superior anti-inflammatory and anti-tumor efficacy compared to metformin. However, the potential role of phenformin in anti-psoriatic skin inflammation has not been explored. METHODS: In this study, we utilized a mouse model of psoriasis and an in vitro model using human keratinocytes to investigate whether phenformin can suppress psoriasis-like inflammatory responses. RESULTS: Our results demonstrate that the topical application of phenformin significantly inhibited acute skin inflammatory responses in the psoriasis mouse model induced by imiquimod (IMQ). Additionally, phenformin suppressed the expression of psoriasis-related cytokines IL-17, IL-23, IL-8, and S100A8/S100A9 in an in vitro psoriatic keratinocyte model induced by IMQ. Furthermore, we found that IMQ-induced psoriatic skin and IMQ-treated keratinocytes exhibited high expression of the c-Myc gene, which was downregulated by phenformin. The c-Myc inhibitor JQ1 similarly inhibited the psoriatic inflammatory response and the expression of psoriasis-related cytokines in both in vitro and in vivo models. CONCLUSION: phenformin ameliorates the psoriasis-like inflammatory response by inhibiting c-Myc expression in keratinocytes, suggesting its potential as a topical drug for the treatment of psoriasis.
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Epidemiological studies have established an association between chronic exposure to PM2.5 and male infertility. However, the underlying mechanisms were not fully revealed. In this study, we established mice models exposed to PM2.5 for 16 weeks, and a significant decrease in sperm quality accompanied by an increase in testosterone levels were observed after PM2.5 exposure. Moreover, treatment with ferrostatin-1 (Fer-1), a specific ferroptosis inhibitor, effectively mitigated PM2.5-induced testicular dysfunction in mice. And lipid peroxidation and ferritin accumulation were found to be significantly increased in Leydig cells of testes with a PM2.5-dose dependent manner. Further investigations revealed that TM-3 cells, a mouse Leydig cell line, were prone to ferroptosis after PM2.5 exposure, and the cell viability was partly rescued after the intervention of Fer-1. Furthermore, our results supported that the ferroptosis of TM-3 cells was attributed to the upregulation of ferredoxin 1 (FDX1), which was the protein transferring electrons to cytochrome P450 family 11 subfamily A member 1 to aid lysing cholesterol to pregnenolone at initial of steroidogenesis. Mechanically, PM2.5-induced FDX1 upregulation resulted in cellular ROS elevation and ferrous iron overload, which together initiated an autoxidation process of polyunsaturated fatty acids in the cell membrane of Leydig cells until the accumulated lipid peroxides triggered ferroptotic cell death. Simultaneously, upregulation of FDX1 promoted steroidogenesis and let to an increased level of testosterone. In summary, our work suggested that FDX1, a mediator involving steroidogenesis, was a key regulator in PM2.5-induced Leydig cells ferroptosis.
Subject(s)
Ferroptosis , Leydig Cells , Male , Mice , Animals , Leydig Cells/metabolism , Semen , Testosterone/metabolism , Particulate Matter/metabolismABSTRACT
BACKGROUND: Congenital anomalies (CAs) are the leading causes for children's disabilities and mortalities worldwide. The associations between air pollution and CAs are not fully characterized in fetuses born by in vitro fertilization (IVF) who are at high risk of congenital anomalies. METHODS: We conducted a cross-sectional study including 16,971 IVF cycles from three hospitals in Hebei Province, China, 2014-2019. Air quality data was obtained from 149 air monitoring stations. Individual average daily concentrations of PM2.5, PM10, NO2, SO2, CO, and O3 were estimated by spatiotemporal kriging method. Exposure windows were divided into 5: preantral follicle period, antral follicle period, germinal period, embryonic period and early fetal period. Logistic generalized estimating equations were used to estimate the associations between air pollutants and overall or organ-system specific congenital anomalies. Negative control exposure method was used to detect and reduce bias of estimation. RESULTS: We found increasing levels of PM2.5 and PM10 were associated with higher risk of overall congenital anomalies during early fetal period, equating gestation 10-12 weeks (OR: 1.05, 95% CI: 1.02-1.09, p = 0.013 for a 10 µg/m3 increase of PM2.5; OR: 1.03, 95% CI: 1.01-1.06, p = 0.021 for a 10 µg/m3 increase of PM10). Cleft lip and cleft palate were associated with PM10 in germinal period and early fetal period. The CAs of eye, ear, face and neck were related to CO in preantral follicle stage. We did not find an association between chromosome abnormalities and air pollution exposure. CONCLUSIONS: We concluded that ambient air pollution was a risk factor for congenital anomalies in the fetuses conceived through IVF, especially exposure in early fetal period.
Subject(s)
Air Pollutants , Air Pollution , Air Pollutants/analysis , Air Pollutants/toxicity , Air Pollution/analysis , Air Pollution/statistics & numerical data , Child , China/epidemiology , Cross-Sectional Studies , Female , Fertilization in Vitro , Humans , Particulate Matter/analysis , Particulate Matter/toxicity , Parturition , PregnancyABSTRACT
Independent component analysis (ICA) is one of the most effective approaches in extracting independent signals from a global navigation satellite system (GNSS) regional station network. However, ICA requires the involved time series to be complete, thereby the missing data of incomplete time series should be interpolated beforehand. In this contribution, a modified ICA is proposed, by which the missing data are first recovered based on the reversible property between the original time series and decomposed principal components, then the complete time series are further processed with FastICA. To evaluate the performance of the modified ICA for extracting independent components, 24 regional GNSS network stations located in North China from 2011 to 2019 were selected. After the trend, annual and semiannual terms were removed from the GNSS time series, the first two independent components captured 17.42, 18.44 and 17.38% of the total energy for the North, East and Up coordinate components, more than those derived by the iterative ICA that accounted for 16.21%, 17.72% and 16.93%, respectively. Therefore, modified ICA can extract more independent signals than iterative ICA. Subsequently, selecting the 7 stations with less missing data from the network, we repeatedly process the time series after randomly deleting parts of the data and compute the root mean square error (RMSE) from the differences of reconstructed signals before and after deleting data. All RMSEs of modified ICA are smaller than those of iterative ICA, indicating that modified ICA can extract more exact signals than iterative ICA.
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BACKGROUND AND OBJECTIVES: Atrial fibrillation (AF) is one of the most common arrhythmias clinically. Aging tends to increase the risk of AF, which also increases the burden of other comorbidities, including coronary artery disease (CAD), and even heart failure (HF). The precise detection of AF is a challenge due to its intermittence and unpredictability. A method for the accurate detection of AF is still needed. METHODS: A deep learning model was used to detect atrial fibrillation. Here, a distinction was not made between AF and atrial flutter (AFL), both of which manifest as a similar pattern on an electrocardiogram (ECG). This method not only discriminated AF from normal rhythm of the heart, but also detected its onset and offset. The proposed model involved residual blocks and a Transformer encoder. RESULTS AND CONCLUSIONS: The data used for training were obtained from the CPSC2021 Challenge, and were collected using dynamic ECG devices. Tests on four public datasets validated the availability of the proposed method. The best performance for AF rhythm testing attained an accuracy of 98.67%, a sensitivity of 87.69%, and a specificity of 98.56%. In onset and offset detection, it obtained a sensitivity of 95.90% and 87.70%, respectively. The algorithm with a low FPR of 0.46% was able to reduce troubling false alarms. The model had a great capability to discriminate AF from normal rhythm and to detect its onset and offset. Noise stress tests were conducted after mixing three types of noise. We visualized the model's features using a heatmap and illustrated its interpretability. The model focused directly on the crucial ECG waveform where showed obvious characteristics of AF.
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Objective: The aim was to study the impact of coronavirus disease 2019 (COVID-19) convalescence on female fertility and laboratory and clinical outcomes in fresh assisted reproductive technology (ART) cycles. Methods: In this retrospective cohort study, we analyzed data from 294 patients who had recovered from COVID-19 and who underwent fresh ART cycles between January and March 2023 (COVID-19 group). This group was compared with 631 patients who underwent similar ART cycles in the same period in 2022 but without having been infected with COVID-19 (non-COVID-19 group). The analysis focused on comparison of basic demographic characteristics and laboratory parameters of patients in each group. The primary outcome measure was the clinical pregnancy rate, which was examined to assess the impact of COVID-19 infection on the efficacy of ART treatment. Results: Basal follicle-stimulating hormone (FSH) levels were significantly lower and antral follicle count (AFC) was markedly higher in the COVID-19 group compared to the non-COVID-19 group (P<0.001 and P=0.004, respectively). The predominant ovarian stimulation protocol in the COVID-19 group was GnRH antagonists (64.85%, P<0.001), with a reduced gonadotropin (Gn) dosage and duration in comparison to the non-COVID-19 group (P<0.05). Although the number of blastocysts formed was lower in the COVID-19 group (P=0.017), this group also exhibited a higher blastocyst freezing rate and a higher rate of high-quality embryos per retrieved oocyte (P<0.001 and P=0.023, respectively). Binary logistic regression analysis indicated that COVID-19 convalescence did not significantly impact clinical pregnancy rates in fresh transfer cycles (odds ratio [OR] = 1.16, 95% confidence interval [CI] = 0.68-1.96, P=0.5874). However, smooth curve-fitting and threshold effect analysis revealed an age-related decline in clinical pregnancy rates in both groups, more pronounced in the COVID-19 group, for women aged over 38 years, with the likelihood of clinical pregnancy decreasing by 53% with each additional year of age (odds ratio [OR] = 0.81, 95% confidence interval [CI] = 0.61-1.08, P=0.1460; odds ratio [OR] = 0.47, 95% CI = 0.21-1.05, P=0.0647). Conclusions: Our findings present no substantial evidence of adverse effects on clinical pregnancy outcomes in fresh ART cycles in patients undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) during the period of convalescence from COVID-19. However, age emerges as a significant factor influencing these outcomes. Notably, for women above 38 years of age, the likelihood of clinical pregnancy in patients with a prior COVID-19 infection decreased by 53% with each additional year. This highlights the importance of considering maternal age, especially in the context of COVID-19, when evaluating the likelihood of successful pregnancy following ART treatments.
Subject(s)
COVID-19 , Pregnancy Outcome , Male , Pregnancy , Humans , Female , Pregnancy Outcome/epidemiology , Sperm Injections, Intracytoplasmic/methods , Retrospective Studies , Convalescence , Live Birth , COVID-19/therapy , Semen , Reproductive Techniques, Assisted , Fertilization in Vitro/methodsABSTRACT
Accumulating evidence has suggested that men exposed to air pollution are associated with decreased sperm quality, and seminal plasma plays a pivotal role in maintaining sperm viability. However, the role of seminal plasma in air pollution related sperm quality decline remain unestablished. In current study, we recruited 524 participants from couples who underwent in vitro fertilization treatment due to female factors at a fertility clinic in China from March to August 2020. Conventional sperm parameters, total antioxidant capacity (T-AOC), malondialdehyde (MDA) and testosterone were measured using semen samples. The six main air pollutants (PM2.5, PM10, NO2, SO2, CO, O3) during four key periods of sperm development (meiotic stage, spermiogenesis stage, epididymal stage and total sperm cycle period) were estimated using inverse distance weighting method. Multiple linear regression models were employed to investigate the exposure-outcome relationships. And we found that PM10 exposures were negatively related to sperm total motility and the exposures of PM2.5 and PM10 were inversely associated with sperm progressive motility during epididymal stage. Furthermore, PM2.5 and PM10 exposures were positively associated with seminal plasma MDA and PM10 was negatively related to seminal plasma T-AOC during epididymal stage. PM2.5, PM10 and CO exposures during total sperm cycle period might relate to increased seminal plasma testosterone. Mediation analysis indicated seminal plasma MDA and T-AOC partially mediated PM10 associated reduction of sperm motility during epididymal stage. Our study suggested MDA and T-AOC of seminal plasma played a role in air pollution associated decline of sperm motility.
Subject(s)
Air Pollutants , Air Pollution , Male , Humans , Female , Semen , Antioxidants/pharmacology , Malondialdehyde/analysis , Particulate Matter/analysis , Sperm Motility , Spermatozoa , Air Pollution/adverse effects , Air Pollution/analysis , Air Pollutants/toxicity , Air Pollutants/analysis , ChinaABSTRACT
Objective: To evaluate the pregnancy outcomes of progestin-primed ovarian stimulation (PPOS) protocol for patients with endometrioma underwent in vitro fertilization/intra-cytoplasmic sperm injection embryo transfer (IVF/ICSI-ET). Design: Observational retrospective cohort study. Setting: University affiliated reproductive center. Study Participants: 605 infertile patients with endometrioma underwent IVF/ICSI-ET from January 2016 to March 2021 were included in this study. Methods: Multivariable logistic regression analyses were conducted to determine the independent effect of controlled ovarian stimulation (COS) protocols on reproductive outcomes of first embryo transfer (ET) cycles. The live birth was primary outcome, the implantation rate, biochemical pregnancy, clinical pregnancy and ongoing pregnancy were secondary outcomes. Results: Compared to PPOS protocol, the probability of implantation showed no significant difference with ultra-long gonadotrophin-releasing hormone agonist (GnRHa) protocol and gonadotrophin-releasing hormone antagonist (GnRHant) protocol (OR 1.7, 95% CI 0.9-3.1, OR 1.2, 95% CI 0.7-2.1, respectively). The PPOS protocol was correlated with a significantly lower biochemical pregnancy and clinical pregnancy than ultra-long GnRHa protocol in the multivariable logistic regression analysis (OR 2.3, 95% CI 1.1-4.9, OR 2.4, 95% CI 1.1-5.3, respectively). However, there was no significant difference in terms of biochemical pregnancy, clinical pregnancy and ongoing pregnancy between PPOS and GnRHant protocol (OR 1.4, 95% CI 0.7-2.7, OR 1.3, 95% CI 0.7-2.4, OR 1.1, 95% CI 0.6-2.3, respectively). In addition, compared to PPOS protocol, ultra-long GnRHa protocol and GnRHant protocol demonstrated no statistical difference in ongoing pregnancy (OR 2.0, 95% CI 0.9-4.5, OR 2.1, 95% CI 0.6-2.3, respectively). Notably, the ultra-long GnRHa protocol was associated with a significant higher probability of live birth than PPOS protocol both in crude analysis and multivariable logistic regression analysis (OR 2.6, 95% CI 1.3-5.1, OR 2.5, 95% CI 1.1-5.7, respectively). Nevertheless, no statistical difference was found in live birth between PPOS and GnRHant protocol either in crude analysis and multivariable logistic regression analysis (OR1.2, 95% CI 0.6-2.3, OR 1.2, 95% CI 0.6-2.5, respectively). Conclusions: Based on the reproductive outcomes of the first ET cycles in patients with endometrioma, PPOS protocol may associated with inferior reproductive outcomes in terms of biochemical pregnancy, clinical pregnancy and live birth than ultra-long GnRHa protocol. However, there was no significant difference in implantation rate, clinical pregnancy, ongoing pregnancy and live birth between PPOS and GnRHant protocol.
Subject(s)
Endometriosis , Progestins , Endometriosis/drug therapy , Female , Fertilization in Vitro/methods , Hormone Antagonists , Humans , Observational Studies as Topic , Ovulation Induction/methods , Pregnancy , Retrospective StudiesABSTRACT
Maternal exposure to air pollution is associated with poor reproductive outcomes in in vitro fertilization (IVF). However, the susceptible time windows are still not been known clearly. In the present study, we linked the air pollution data with the information of 9001 women receiving 10,467 transfer cycles from August 2014 to August 2019 in The Second Hospital of Hebei Medical University, Shijiazhuang City, China. Maternal exposure was presented as individual average daily concentrations of PM2.5, PM10, NO2, SO2, CO, and O3, which were predicted by spatiotemporal kriging model based on residential addresses. Exposure windows were divided to five periods according to the process of follicular and embryonic development in IVF. Generalized estimating equation model was used to evaluate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for association between clinical pregnancy and interquartile range increased average daily concentrations of pollutants during each exposure period. The increased PM2.5 (adjusted OR = 0.95, 95% CI: 0.90, 0.99), PM10 (adjusted OR = 0.93, 95% CI: 0.89, 0.98), NO2 (adjusted OR = 0.89, 95% CI: 0.85, 0.94), SO2 (OR = 0.94, 95% CI: 0.90, 0.98), CO (adjusted OR = 0.93, 95% CI: 0.89, 0.97) whereas decreased O3 (OR = 1.08, 95% CI: 1.02, 1.14) during the duration from preantral follicles to antral follicles were the strongest association with decreased probability of clinical pregnancy among the five periods. Especially, women aged 20-29 years old were more susceptible in preantral-antral follicle transition stage. Women aged 36-47 years old were more vulnerable during post-oocyte retrieve period. Our results suggested air pollution exposure during preantral-antral follicle transition stage was a note-worthy challenge to conceive among females receiving IVF.