FERREG: ferroptosis-based regulation of disease occurrence, progression and therapeutic response.

Ferroptosis is a non-apoptotic, iron-dependent regulatory form of cell death characterized by the accumulation of intracellular reactive oxygen species. In recent years, a large and growing body of literature has investigated ferroptosis. Since ferroptosis is associated with various physiological activities and regulated by a variety of cellular metabolism and mitochondrial activity, ferroptosis has been closely related to the occurrence and development of many diseases, including cancer, aging, neurodegenerative diseases, ischemia-reperfusion injury and other pathological cell death. The regulation of ferroptosis mainly focuses on three pathways: system Xc-/GPX4 axis, lipid peroxidation and iron metabolism. The genes involved in these processes were divided into driver, suppressor and marker. Importantly, small molecules or drugs that mediate the expression of these genes are often good treatments in the clinic. Herein, a newly developed database, named 'FERREG', is documented to (i) providing the data of ferroptosis-related regulation of diseases occurrence, progression and drug response; (ii) explicitly describing the molecular mechanisms underlying each regulation; and (iii) fully referencing the collected data by cross-linking them to available databases. Collectively, FERREG contains 51 targets, 718 regulators, 445 ferroptosis-related drugs and 158 ferroptosis-related disease responses. FERREG can be accessed at https://idrblab.org/ferreg/.

Body-mass index and obesity in infertile couples in southwest China.

To investigate body mass index (BMI) of infertile couples and analyze its related influencing factors in Southwest China, so as to prevent and control the obesity. We analyzed the data of a total number of 8877 infertile couples who received treatment in our assisted reproductive center from October 2012 to March 2022. The mean age and BMI of men and women were 33.5 years, 23.9 kg/m2 and 31.6 years, 21.9 kg/m2. The prevalence of overweight (BMI 25-29.9) was 30.9% in men and 14.7% in women, 3.7% of men and 1.6% of women were obese (BMI ≥ 30), while 3.6% of men and 10.8% of women were underweight (BMI<18.5). Multivariable linear regression analysis indicated that the age and educational background of both women and men had an impact on BMI. In our study, the proportion of male obesity and overweight is much higher than that of female. On the other hand, the proportion of females with low weight was higher than that of males. The age and educational background of men and women have a certain correlation with BMI.

Ginsenoside Rg3 alleviates the migration, invasion, and angiogenesis of lung cancer cells by inhibiting the expressions of cyclooxygenase-2 and vascular endothelial growth factor.

Lung cancer (LC) is a common cancer with high incidence and mortality rates. In recent years, ginsenoside Rg3 (Rg3), a traditional medicine, is widely used for the treatment of LC. Herein, we concentrate on assessing the effect of Rg3 on LC cell migration and invasion. The effects of Rg3 (0, 25, 50, and 100 µg/ml) on the viability, migration, invasion, angiogenesis, and expressions of epithelial-mesenchymal transition (EMT)-related proteins, cyclooxygenase-2 (COX2), and vascular endothelial growth factor (VEGF) of LC cell lines were evaluated by cell counting kit-8 (CCK-8), scratch, transwell, tube formation, and western blot assays. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to assess transfection efficiency. COX2 overexpression plasmid and short hairpin RNA for VEGF (shVEGF) were applied to evaluate whether the effect of Rg3 is related to COX2 and VEGF through rescue assay. In this study, Rg3 significantly dose-dependently suppressed the viability, migration, invasion, angiogenesis, and protein expressions of N-cadherin, vimentin, COX2, and VEGF in H1299 and A549 cells, while promoting the expression of E-cadherin protein. COX2 overexpression markedly reversed the effects of Rg3 on the viability, migration, invasion, angiogenesis, and EMT-related protein expression levels in LC cells; however, such effects of COX2 overexpression were offset by VEGF knockdown. In sum, Rg3 alleviates the migration, invasion, and angiogenesis of LC cells by inhibiting the expressions of COX2 and VEGF.

Co-administration of tacrolimus and low molecular weight heparin in patients with a history of implantation failure and elevated peripheral blood natural killer cell proportion.

AIM: To investigate the therapeutic effect of co-administration of tacrolimus (TAC) and low-molecular-weight heparin (LMWH) or LMWH only on pregnancy outcomes in the female with a history of implantation failure and elevated peripheral blood natural killer (pNK) cell proportion in frozen-thawed embryo transfer cycles. METHODS: To evaluate the pregnancy parameters for 249 patients with ≥2 implantation failures and pNK cell proportion ≥12% by analyzing a retrospective observational cohort study. Sixty patients had received the co-administration TAC and LMWH (TAC & LMWH group), 85 others had only taken LMWH (LWMH group), and the rest did not take any particular drugs (control group). RESULTS: The experimental finding indicated that the TAC & LMWH group and the LMWH group showed higher clinical pregnancy rates than the control group (p < 0.05), and TAC & LMWH group had a much higher live birth rate. According to the binary logistic regression analysis, the combination of TAC and LMWH was conducive to clinical pregnancy and live birth rate and reduced the possibility of miscarriage. It would not affect the result of spontaneous abortion and live birth, although the LMWH was only beneficial to clinical pregnancy. In addition, these findings were similar for these three groups' obstetrical and neonatal outcomes. CONCLUSIONS: The combination of TAC and LMWH can improve clinical pregnancy and live birth rates and reduce the risk of spontaneous miscarriage in patients with a history of implantation failure and elevated pNK ratio. LMWH is also beneficial to clinical pregnancy.

Evaluation of Clinical Outcomes of Icotinib in Patients With Clinically Diagnosed Advanced Lung Cancer With EGFR-Sensitizing Variants Assessed by Circulating Tumor DNA Testing: A Phase 2 Nonrandomized Clinical Trial.

Importance: The inability to obtain a pathological diagnosis in a certain proportion of patients with clinically diagnosed advanced lung cancer impedes precision treatment in clinical practice. Objective: To evaluate the clinical outcome of first-line icotinib in patients with clinically diagnosed advanced lung cancer with unknown pathological status and positive epidermal growth factor receptor (EGFR)-sensitizing variants assessed by circulating tumor DNA (ctDNA). Design, Setting, and Participants: The Efficiency of Icotinib in Plasma ctDNA EGFR Mutation-Positive Patients Diagnosed With Lung Cancer (CHALLENGE) trial is a prospective, multicentered, open-label, single-arm phase 2 nonrandomized clinical trial conducted between July 1, 2017, and July 31, 2019. Patients with systemic treatment-naive, clinically diagnosed advanced peripheral lung cancer, unknown pathological status, and positive pretreatment plasma EGFR-sensitizing variants were eligible. A total of 391 potentially eligible Chinese patients from 19 centers in China were screened for ctDNA EGFR variants by 3 independent detection platforms (Super amplification refractory mutation system [SuperARMS] polymerase chain reaction, droplet digital polymerase chain reaction, and next-generation sequencing), and those with EGFR variants tested by any platform were included. Analyses were conducted from September 9 to December 31, 2021. Interventions: Enrolled patients were treated with oral icotinib tablets (125 mg 3 times daily) until disease progression, death, or treatment discontinuation due to various reasons, such as toxic effects and withdrawing consent. Main Outcomes and Measures: The primary end point was objective response rate (ORR). The secondary end points included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and the concordance among the 3 detection platforms. Results: Of 116 included patients, 76 (65.5%) were female, and the median (range) age was 64 (37-85) years. The median (IQR) follow-up duration was 36.3 (30.2-40.7) months. The ORR was 52.6% (95% CI, 43.1%-61.9%). The median PFS and OS were 10.3 months (95% CI, 8.3-12.2) and 23.2 months (95% CI, 17.7-28.0), respectively, and the DCR was 84.5% (95% CI, 76.6%-90.5%). The concordance rate among the 3 detection platforms was 80.1% (313 of 391), and the clinical outcomes in patients identified as positive by any platform were comparable. Conclusions and Relevance: This prospective phase 2 nonrandomized clinical trial suggests that for patients with clinically diagnosed advanced lung cancer with unknown pathological status, ctDNA-based EGFR genotyping could help decision-making in particular clinical situations, while still warranting future larger-scaled real-world exploration. Trial Registration: ClinicalTrials.gov Identifier: NCT03346811.

Brain circuit dysfunction in specific symptoms of depression.

Since the depressive disorder manifests complex and diverse symptoms clinically, its pathological mechanism and therapeutic options are difficult to determine. In recent years, the advent of optogenetics, chemogenetics and viral tracing techniques, along with the well-established rodent model of depression, has led to a shift in the focus of depression research from single molecules to neural circuits. In virtue of the powerful tools above, psychiatric disorder such as depression could be well related to the disfunction of brain's connection. Moreover, compelling studies also support that the diversity of depressive behaviour could be involved with the discrete changes in a distinct circuit of the brain. Therefore, summarising the differential changes of the neural circuits in mice with depression-like behaviour may provide a better understanding of the causal relationships between neural circuit and depressive behaviour. Here, we focus on the changes in the neural circuitry underlying various depression-like phenotypes, including motivation, despair, social avoidance and comorbid sequelae, which may provide an explanation to circuit-specific discrepancy in depression-like behaviour.

Sortilin deletion in the prefrontal cortex and hippocampus ameliorates depressive-like behaviors in mice via regulating ASM/ceramide signaling.

Major depressive disorder (MDD) is a common psychiatric disorder characterized by persistent mood despondency and loss of motivation. Although numerous hypotheses have been proposed, the possible pathogenesis of MDD remains unclear. Several recent studies show that a classic transporter protein, sortilin, is closely associated with depression. In the present study, we investigated the role of sortilin in MDD using a well-established rodent model of depression. Mice were subjected to chronic unpredictable mild stress (CUMS) for 6 weeks. We showed that the expression levels of sortilin were significantly increased in the prefrontal cortex and hippocampus of CUMS mice. The depressive-like behaviors induced by CUMS were alleviated by specific knockdown of sortilin in the prefrontal cortex and hippocampus. We revealed that sortilin facilitated acid sphingomyelinase (ASM)/ceramide signaling, which activated RhoA/ROCK2 signaling, ultimately causing the transformation of dendritic spine dynamics. Specific overexpression of sortilin in the prefrontal cortex and hippocampus induced depressive-like behaviors, which was mitigated by injection of ASM inhibitor SR33557 (4 µg/µL) into the prefrontal cortex and hippocampus. In conclusion, sortilin knockdown in the prefrontal cortex and hippocampus plays an important role in ameliorating depressive-like behavior induced by CUMS, which is mainly evidenced by decreasing the trafficking of ASM from the trans-Golgi network to the lysosome and reducing the ceramide levels. Our results provide a new insight into the pathology of depression, and demonstrate that sortilin may be a potential therapeutic target for MDD.

Single blastocyst stage versus single cleavage stage embryo transfer following fresh transfer: A systematic review and meta-analysis.

OBJECTIVES: To compare the available evidence of the effectiveness of single blastocyst stage transfer against the effectiveness of single cleavage stage embryo transfer. STUDY DESIGN: A systematic research based on Pubmed, Embase and the Cochrane Library was performed until May 2, 2020 to identify all relevant studies. The Cochrane Collaboration's Review Manager (RevMan) 5.0.2 software was used for statistical analysis. RESULTS: Five randomized controlled trials (RCTs) were included in analysis, involving 1784 patients in total, who were divided into 2 groups, which were the single blastocyst stage transfer (SBT) group of 932, and the single cleavage stage transfer (SCT) group of 852. Our meta-analysis concluded that SBT group had a significantly higher clinical pregnancy rate (RR 1.26; 95%CI: 1.14-1.39), ongoing pregnancy rate (RR 1.19; 95%CI: 1.05-1.35) and delivery rate (RR 1.4; 95%CI: 1.13-1.75) than SCT group during the fresh transfer. While miscarriage rate (RR 0.93; 95% CI: 0.66-1.33), multiple pregnancy rate (RR, 1.12; 95% CI, 0.51-2.45) and ectopic pregnancy rate (RR, 0.5; 95% CI: 0.13-1.90) between two groups showed no significant difference. However, the SCT group contained notably more cryopreserved embryos than the SBT group. (RR -0.68, 95% CI: -0.95 to -0.41). CONCLUSIONS: Our results indicate that single blastocyst stage transfer is associated with higher ongoing pregnancy rate and delivery rate comparing to single cleavage stage transfer in the clinical practice. Due to the low quality of the evidence of the primary outcomes, other higher-quality lager RCTs are necessary before a fully informed decision is made.

Associations of FSHR and LHCGR gene variants with ovarian reserve and clinical pregnancy rates.

RESEARCH QUESTION: Are there any associations between the variants of FSHR c.2039 G>A (p. Ser680Asn, rs6166) and LHCGR c.935A>G (p. Asn312Ser, rs2293275) and ovarian reserve, ovarian response, clinical pregnancy rate and POSEIDON group? DESIGN: A total of 210 infertile women were enrolled in this prospective study. The gene variants were analysed by the Sanger method. The clinical parameters were analysed based on genotypes. RESULTS: The frequency of heterozygous and homozygous G allele for FSHR c.2039 G>A in the low prognosis group was significantly higher than that in other response groups (P = 0.034); there was no significant association between LHCGR c.935 A>G and ovarian response. Moreover, the serum anti-Müllerian hormone (AMH) concentration, antral follicle count (AFC), oocytes retrieved, metaphase II (MII) oocytes and two-pronuclear (2PN) oocytes in patients with AG genotype for FSHR c.2039 G>A were significantly lower than those with AA genotype. The serum LH concentrations and clinical pregnancy rate of fresh embryo transfer in patients with GG genotype for LHCGR c.935 A>G were significantly higher than that of the AG genotype. In POSEIDON analysis, the low prognosis women with AA genotype for FSHR c.2039 G>A were more likely to appear in subgroup 1 (P = 0.038). CONCLUSION: The FSHR c.2039 G>A variant has a significant beneficial influence on ovarian reserve and ovarian response. The LHCGR c.935 A>G variant is associated with increased clinical pregnancy rate of fresh embryo transfer in infertile women. In addition, the low prognosis women with AA genotype for FSHR c.2039 G>A tend to show better ovarian reserve and prognosis.

Influence Factors of Sexual Intercourse Frequency in Infertile Couples without Sexual Dysfunction in Southwest China: A Retrospective Study.

INTRODUCTION: The aim of this study was to investigate the sexual intercourse frequency (SIF) of infertile couples without sexual dysfunction and analyze its related influencing factors. MATERIALS AND METHODS: We retrospectively analyzed the data of a total number of 4,923 infertile couples without sexual dysfunction who received treatment in our assisted reproductive center from October 2016 to October 2018. Both partners of couples were inquired about their information of demographic statistics, occupations, lifestyles, education backgrounds, psychological characteristics, and testostrone levels of male patients. The multivariable linear regression analysis was applied to evaluate the influence of various variables on SIF. RESULTS: The median (interquartile range) SIF of infertile couples without sexual dysfunction was 7 (6.5-8) times per month. Lower academic qualification and younger age were predictive of increased SIF in both partners. The SIF of Chinese Han women and Chinese Zang women is higher than that of other ethnic groups. Men with lower testosterone (<10 nmol/L) were associated with lower SIF. The BMI, occupation, alcohol consumption, races of both partners of couples, and smoking status of males were not associated with SIF. Multivariable linear regression analysis indicated that only the age and the education level of men played an important role in SIF, and educational level of men had the greatest impact, followed by men's age. CONCLUSION: In our study, we analyzed demographics data, occupational characteristics, and lifestyle behaviors of both partners, as well as men's testosterone levels; we also reported the related SIF. According to our research, men's education level was the most important factor in predicting SIF, followed by men's age. Testosterone levels of men do not appear to play a substantial role in predicting SIF in infertile couples.

Indacaterol/glycopyrronium affects lung function and cardiovascular events in patients with chronic obstructive pulmonary diseases: A meta-analysis.

BACKGROUND: Bronchodilators are the cornerstone for treating patients with chronic obstructive pulmonary diseases (COPD), although some studies have shown that dual bronchodilators may exacerbate incidence of adverse cardiovascular events. Here, we evaluated the cardiopulmonary safety of indacaterol/glycopyrronium (IND/GLY) using a meta-analysis. METHODS: We searched PubMed, OVID, Cochrane Library and Web of Science databases, using "indacaterol/glycopyrronium", "indacaterol/glycopyrrolate", "IND/GLY", "QVA149", "chronic obstructive pulmonary diseases", "COPD", "chronic obstructive airway disease", "chronic obstructive lung disease" as key words. Acute exacerbation of COPD and FEV1 as indicators of pulmonary function and occurrence of hypertension, atrial fibrillation, myocardial infarction and heart failure as indicators of cardiovascular safety. RESULTS: A total of 23 articles, comprising 21,238 participants, were included in the analysis. FEV1 values were significantly different compared to IND/GLY and single bronchodilator therapy (LABA or LAMA), with the MD 0.11 L (95%CI: 0.10-0.13, P<0.01). Hypertension was more frequent in the IND/GLY, than the single bronchodilator therapy group, although this difference was insignificant (IND/GLY vs LABA, RR=1.88, P = 0.09; IND/GLY vs LAMA, RR=1.42, P = 0.08; IND/GLY vs LABA+ICS, RR=1.85, P = 0.23). In addition, IND/GLY did not significantly increase the risk of myocardial infarction (IND/GLY vs LAMA or double therapy, total RR: 1.49, 95%CI: 0.72-3.08, P = 0.28), atrial fibrillation (IND/GLY vs LAMA, RR: 1.62, 95%CI: 0.64-4.10, P = 0.31) and heart failure (IND/GLY vs LAMA, RR: 0.40, 95%CI: 0.07-2.33, P = 0.31) in COPD patients. CONCLUSIONS: IND/GLY significantly reduced incidence of acute COPD exacerbations, and slowed down the decline of FEV1. Adequate safety measures are needed to control incidence of adverse cardiovascular events.

Biological functions of m6A methyltransferases.

M6A methyltransferases, acting as a writer in N6-methyladenosine, have attracted wide attention due to their dynamic regulation of life processes. In this review, we first briefly introduce the individual components of m6A methyltransferases and explain their close connections to each other. Then, we concentrate on the extensive biological functions of m6A methyltransferases, which include cell growth, nerve development, osteogenic differentiation, metabolism, cardiovascular system homeostasis, infection and immunity, and tumour progression. We summarize the currently unresolved problems in this research field and propose expectations for m6A methyltransferases as novel targets for preventive and curative strategies for disease treatment in the future.

Discovering the Role of FZD4 Gene in Human Cutaneous Squamous Cell Carcinoma.

BACKGROUND: Frizzled 4 (FZD4) is an important receptor for Wnt proteins that stimulate several downstream signaling pathways. It has been known that the FZD4-Wnt interaction is involved in many types of cancers. However, the role of FZD4 in cutaneous squamous cell carcinoma (CSCC) has not been well studied. AIMS: We sought to investigate the association between FZD4 expression level and tumor cell proliferation and apoptosis rates in CSCC. METHODS: Expression of FZD4 at mRNA level in CSCC tissues and controls was measured. Colo16 cell proliferation and viability were measured by CCK-8 assay and flow cytometry respectively after siRNA and plasmid transfection. RESULTS: We discovered a significant downregulation of FZD4 expression in CSCC tissues and cell lines compared to controls. Furthermore, our data suggested that over expression of FZD4 inhibited proliferation and promoted apoptosis of Colo16 cells. CONCLUSION: The results indicated that FZD4 may play as a tumor suppressor gene in the pathogenesis of CSCC.

The mechanism of m6A methyltransferase METTL3-mediated autophagy in reversing gefitinib resistance in NSCLC cells by ß-elemene.

N6-methyladenosine (m6A) modification can alter gene expression by regulating RNA splicing, stability, translocation, and translation. Emerging evidence shows that m6A modification plays an important role in cancer development and progression, including cell proliferation, migration and invasion, cell apoptosis, autophagy, and drug resistance. Until now, the role of m6A modification mediated autophagy in cancer drug resistance is still unclear. In this study, we found that m6A methyltransferase METTL3-mediated autophagy played an important role in reversing gefitinib resistance by ß-elemene in non-small cell lung cancer (NSCLC) cells. Mechanistically, in vitro and in vivo studies indicated that ß-elemene could reverse gefitinib resistance in NSCLC cells by inhibiting cell autophagy process in a manner of chloroquine. ß-elemene inhibited the autophagy flux by preventing autophagic lysosome acidification, resulting in increasing expression of SQSTM1 and LC3B-II. Moreover, both ß-elemene and gefitinib decreased the level of m6A methylation of gefitinib resistance cells. METTL3 was higher expressed in lung adenocarcinoma tissues than that of paired normal tissues, and was involved in the gefitinib resistance of NSCLC cells. Furthermore, METTL3 positively regulated autophagy by increasing the critical genes of autophagy pathway such as ATG5 and ATG7. In conclusion, our study unveiled the mechanism of METTL3-mediated autophagy in reversing gefitinib resistance of NSCLC cells by ß-elemene, which shed light on providing potential molecular-therapy target and clinical-treatment method in NSCLC patients with gefitinib resistance.

METTL3 plays multiple functions in biological processes.

N6-methyladenosine (m6A) is the most common internal modification of mRNAs in higher eukaryotic. This process is performed by methyltransferase. Methyltransferase-like 3 (METTL3) is the best known m6A methyltransferase that functions in the reversible epi-transcriptome modulation of m6A modification. Besides acting as a m6A methyltransferase, METTL3 also regulates mRNA translation and other biological processes. In recent years, studies have identified numerous roles and molecular mechanisms associated with METTL3 in multiple biological processes. However, these findings have not been summarized. In this review, we have systematically summarized the most recent important roles of METTL3 in various biological processes, including cell cycle progression, cell proliferation, cell apoptosis, cell migration and invasion, cell differentiation and inflammatory response. In addition, we discuss the prospect of using a METTL3 as a new diagnostic biomarker and therapeutic target for human cancers.

UVB induces cutaneous squamous cell carcinoma progression by de novo ID4 methylation via methylation regulating enzymes.

BACKGROUND: Little is known about whether UVB can directly influence epigenetic regulatory pathways to induce cutaneous squamous cell carcinoma (CSCC). This study aimed to identify epigenetic-regulated signalling pathways through global methylation and gene expression profiling and to elucidate their function in CSCC development. METHODS: Global DNA methylation profiling by reduced representation bisulfite sequencing (RRBS) and genome-wide gene expression analysis by RNA sequencing (RNA-seq) in eight pairs of matched CSCC and adjacent normal skin tissues were used to investigate the potential candidate gene(s). Clinical samples, animal models, cell lines, and UVB irradiation were applied to validate the mechanism and function of the genes of interest. FINDINGS: We identified the downregulation of the TGF-ß/BMP-SMAD-ID4 signalling pathway in CSCC and increased methylation of inhibitor of DNA binding/differentiation 4 (ID4). In normal human and mouse skin tissues and cutaneous cell lines, UVB exposure induced ID4 DNA methylation, upregulated DNMT1 and downregulated ten-eleven translocation (TETs). Similarly, we detected the upregulation of DNMT1 and downregulation of TETs accompanying ID4 DNA methylation in CSCC tissues. Silencing of DNMT1 and overexpression of TET1 and TET2 in A431 and Colo16 cells led to increased ID4 expression. Finally, we showed that overexpression of ID4 reduced cell proliferation, migration, and invasion, and increased apoptosis in CSCC cell lines and reduced tumourigenesis in mouse models. INTERPRETATION: The results indicate that ID4 is downregulated by UVB irradiation via DNA methylation. ID4 acts as a tumour suppressor gene in CSCC development. FUNDING: CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-3-021, 2017-I2M-1-017), the Natural Science Foundation of Jiangsu Province (BK20191136), and the Fundamental Research Funds for the Central Universities (3332019104).

Pirfenidone alleviates pulmonary fibrosis in vitro and in vivo through regulating Wnt/GSK-3ß/ß-catenin and TGF-ß1/Smad2/3 signaling pathways.

BACKGROUND: Pirfenidone (PFD) is effective for pulmonary fibrosis (PF), but its action mechanism has not been fully explained. This study explored the signaling pathways involved in anti-fibrosis role of PFD, thus laying a foundation for clinical application. METHODS: Pulmonary fibrosis mice models were constructed by bleomycin (BLM), and TGF-ß1 was used to treat human fetal lung fibroblasts (HLFs). Then, PFD was added into treated mice and cells alone or in combination with ß-catenin vector. The pathological changes, inflammatory factors levels, and Collagen I levels in mice lung tissues were assessed, as well as the activity of HLFs was measured. Levels of indices related to extracellular matrix, epithelial-mesenchymal transition (EMT), Wnt/GSK-3ß/ß-catenin and TGF-ß1/Smad2/3 signaling pathways were determined in tissues or cells. RESULTS: After treatment with BLM, the inflammatory reaction and extracellular matrix deposition in mice lung tissues were serious, which were alleviated by PFD and aggravated by the addition of ß-catenin. In HLFs, PFD reduced the activity of HLFs induced by TGF-ß1, inhibited levels of vimentin and N-cadherin and promoted levels of E-cadherin, whereas ß-catenin produced the opposite effects to PFD. In both tissues and cells, Wnt/GSK-3ß/ß-catenin and TGF-ß1/Smad2/3 signaling pathways were activated, which could be suppressed by PFD. CONCLUSIONS: PFD alleviated pulmonary fibrosis in vitro and in vivo through regulating Wnt/GSK-3ß/ß-catenin and TGF-ß1/Smad2/3 signaling pathways, which might further improve the action mechanism of anti-fibrosis effect of PFD.

Microsurgical gonadal-inferior epigastric vein anastomosis to treat the nutcracker phenomenon with left gonadal vein varices with reflux.

OBJECTIVE: To evaluate the effectiveness and safety of microsurgical gonadal-inferior epigastric vein anastomosis for the treatment of the nutcracker phenomenon (NCP) associated with left gonadal vein varices with reflux. METHODS: Thirty-five patients with NCP associated with left gonadal vein varices with reflux diagnosed in our hospital from June 2016 to June 2018 were included. All patients underwent a shunt operation consisting of microsurgical gonadal-inferior epigastric vein anastomosis, and the patients were followed up for 1 year. RESULTS: All patients were successfully operated on, with an average operation time of 96.5 ± 12.3 min. After a 1-year follow-up, the symptom of gross hematuria disappeared in 3 patients (including 1 woman). For the other 32 patients, the sperm concentration (27.43 ± 8.68 × 106/ml) and motility (33.06 ± 4.27%) postoperatively were significantly higher than that preoperatively (16.21 ± 6.43 × 106/ml and 23.48 ± 4.43%, respectively) (P < 0.05); among these patients, 2 had natural pregnancies with their spouses. The peak velocity (PV) at the aortomesenteric portion of the left renal vein (LRV) and the PV ratio between the aortomesenteric and hilar portion of the LRV significantly decreased after surgery (117.9 ± 30.4 cm/s vs 76.6 ± 18.5 cm/s; 7.3 ± 0.7 vs 4.1 ± 0.4). Two patients had complications of mild hydroceles requiring no intervention, and no major complications were observed during and after surgery. CONCLUSION: Our results suggest that the microsurgical gonadal-inferior epigastric vein anastomosis is both effective and safe to treat patients with gonadal varicose veins caused by the nutcracker phenomenon.