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Bromadiolone, a widely-used rodent control drug, could act as a long-acting anticoagulant. Patients of bromadiolone poisoning often present with multiorgan hemorrhage. However, neurological symptoms of bromadiolone poisoning are seldom reported. We report a rare case with convulsive status epilepticus as the initial presentation of bromadiolone poisoning. A previously healthy 18-year-old man presented with persistent unconsciousness and repeated convulsive seizures. Magnetic resonance imaging revealed lesions in the corpus callosum. Laboratory test revealed the microscopic hematuria, prolonged prothrombin time, prolonged activated partial thromboplastin time and the presence of bromadiolone. The patient was diagnosed as the bromadiolone poisoning and treated with hemofiltration, vitamin K and prothrombin complex. Consciousness of the patient was regained and all neurological symptoms diminished after 7 days. Coagulopathy was totally corrected after 3 weeks, and a 2-month regimen of vitamin K supplementation was prescribed after discharge. Our case suggests that bromadiolone poisoning may involve the central nervous system. The atypical and initial symptoms of neurological disorders might lead to misdiagnosis of bromadiolone poisoning. Poisoning should be considered when acute neurological symptoms are combined with bleeding tendency. The vitamin K treatment is effective for both coagulopathy and central nervous system disorders in bromadiolone poisoning.

The search for therapeutic targets for Parkinson’s disease (PD) is hindered by the incomplete understanding of the pathophysiology of the disease. Mitochondrial dysfunction is an area with high potential. The neurobiological signaling connections between the gut microbiome and the central nervous system are incompletely understood. Multiple lines of evidence suggest that the gut microbiota participates in the pathogenesis of PD. Gut microbial dysbiosis may contribute to the loss of dopaminergic neurons through mitochondrial dysfunction. The intervention of gut microbial metabolites via the microbiota-gut-brain axis may serve as a promising therapeutic strategy for PD. In this narrative review, we summarize the potential roles of gut microbial dysbiosis in PD, with emphasis on microbial metabolites and mitochondrial function. We then review the possible ways in which microbial metabolites affect the central nervous system, as well as the impact of microbial metabolites on mitochondrial dysfunction. We finally discuss the possibility of gut microbiota as a therapeutic target for PD.

To explore the effectiveness of Danhong Injection (丹红注射液) on improving microcirculatory injury after percutaneous coronary intervention (PCI) in patients with coronary heart disease (CHD). A randomized controlled trial was conducted and 90 patients were enrolled. A random sequence was generated using statistical analysis software. Patients with microcirculatory injuries after PCI were randomly divided into 3 groups for treatment (30 subjects in each group): Danhong Injection group: after PCI, Danghong Injections were given with intravenous administration with 40 mL twice a day for a week; statins intensive group: after PCI, atorvastatin calcium tablets were given oral medication with 80 mg once, and then atorvastatin 40 mg daily for 1 week; the control group: after PCI, atorvastatin calcium tablets were given oral medication with 10–20 mg daily for 1 week. The index of microcirculation resistance (IMR) was used to assess microcirculatory injury during PCI. The IMR of the target vessel was reexamined after 1 week of drug treatment. After one week’s drug treatment, IMR was significantly decreased in both statins intensive group and Danhong Injection group compared with the control group (P

Understanding how gut flora influences gut-brain communications has been the subject of significant research over the past decade. The broadening of the term “microbiota-gut-brain axis” from “gut-brain axis” underscores a bidirectional communication system between the gut and the brain. The microbiota-gut-brain axis involves metabolic, endocrine, neural, and immune pathways which are crucial for the maintenance of brain homeostasis. Alterations in the composition of gut microbiota are associated with multiple neuropsychiatric disorders. Although a causal relationship between gut dysbiosis and neural dysfunction remains elusive, emerging evidence indicates that gut dysbiosis may promote amyloid-beta aggregation, neuroinflammation, oxidative stress, and insulin resistance in the pathogenesis of Alzheimer’s disease (AD). Illustration of the mechanisms underlying the regulation by gut microbiota may pave the way for developing novel therapeutic strategies for AD. In this narrative review, we provide an overview of gut microbiota and their dysregulation in the pathogenesis of AD. Novel insights into the modification of gut microbiota composition as a preventive or therapeutic approach for AD are highlighted.

We performed this study to evaluate the clinical outcomes of microdissection testicular sperm extraction-intracytoplasmic sperm injection (micro-TESE-ICSI) treatment that used fresh or cryopreserved sperm in patients with nonobstructive azoospermia (NOA). A total of 338 NOA patients with 344 consecutive cycles received treatment in the reproductive medicine center of Peking University Third Hospital in Beijing, China, from January 2014 to December 2017. Fresh oocytes and fresh sperm were used in 222 patients with 234 cycles (Group A). Fresh oocytes and cryopreserved sperm were used in 116 patients with 110 cycles (Group B). We compared patient characteristics, embryonic development, and pregnancy outcomes between Groups A and B. There was no statistical difference in the patient characteristics, and no differences were observed with fertilization or quality embryo rates between Groups A and B. The rates of clinical pregnancy and live birth were both higher for Group A than those for Group B (both P < 0.05). In conclusion, fresh testicular sperm appears to produce better ICSI outcomes than cryopreserved testicular sperm in patients with NOA.

Axonal variants of Guillain-Barre syndrome (GBS) mainly include acute motor axonal neuropathy, acute motor and sensory axonal neuropathy, and pharyngeal-cervical-brachial weakness. Molecular mimicry of human gangliosides by a pathogen's lipooligosaccharides is a well-established mechanism for Campylobacter jejuni-associated GBS. New triggers of the axonal variants of GBS (axonal GBS), such as Zika virus, hepatitis viruses, intravenous administration of ganglioside, vaccination, and surgery, are being identified. However, the pathogenetic mechanisms of axonal GBS related to antecedent bacterial or viral infections other than Campylobacter jejuni remain unknown. Currently, autoantibody classification and serial electrophysiology are cardinal approaches to differentiate axonal GBS from the prototype of GBS, acute inflammatory demyelinating polyneuropathy. Newly developed technologies, including metabolite analysis, peripheral nerve ultrasound, and feature selection via artificial intelligence are facilitating more accurate diagnosis of axonal GBS. Nevertheless, some key issues, such as genetic susceptibilities, remain unanswered and moreover, current therapies bear limitations. Although several therapies have shown considerable benefits to experimental animals, randomized controlled trials are still needed to validate their efficacy.

The coronavirus disease 2019 (COVID-19) started on 12 December 2019 in Wuhan, China, had caused 7,885,123 cases including 431,835 deaths by 14 Jun 2020 all over the world. Here we report the genomic characterization and phylogenetic evolution of this coronavirus called SARS-CoV-2 that caused COVID-19. The SARS-CoV-2 genomes and other coronaviruses were obtained from GISAID and GenBank. Then the genome was annotated, and potential genetic recombination was investigated. Phylogenetic analysis was conducted and used to determine the evolutionary history of the virus and help deduce the origin of virus. An annotation has revealed SARS-CoV-2 possessed a similar genomic organisation to bat-SARS-like-CoV collected in China. The genome sequences of SARS-CoV-2 were very similar, showing 99.6-100% sequence identity. Notably, SARS-CoV-2 was closely related (with 88% identity) to bat-SARS-like coronavirus, but was more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%). Phylogenetic tree of the complete viral genome showed that the virus clustered with bat SARS-like coronavirus. The results of the similarity between SARS-CoV-2 and related viruses did not identify any potential genomic recombination events. Therefore, it seems like that the SARS-CoV-2 might be originally hosted by bats, and might have been transmitted to humans via intermediate hosts of currently unknown wild animal(s). Finally, based on the wide spread of SARS-CoV in their natural reservoirs, future studies should focus more on surveillance of coronavirus, and measures against the domestication and consumption of wild animals should be implemented. Keywords: coronavirus; SARS coronavirus; SARS-CoV-2; genomic characterization; phylogenetic evolution.

Introduction Enolases are enzymes in the glycolytic pathway, which catalyse the reversible conversion of D-2-phosphoglycerate into phosphoenol pyruvate in the second half of the pathway. In this research, the effects of α-enolase (ENO1) on steroid reproductive-related hormone receptor expression and on hormone synthesis of primary granulosa cells from goose F1 follicles were studied. Material and Methods Primary granulosa cells from the F1 follicles of eight healthy 8-month-old Zi geese were separated and cultured. An ENO1 interference expression vector was designed, constructed and transfected into primary cultured granulosa cells. The mRNA expression levels of follicle-stimulating hormone receptor (FSHR), luteinising hormone receptor (LHR), oestrogen receptor α (ER α), oestrogen receptor β (ER β), growth hormone receptor (GHR) and insulin-like growth factor binding protein-1 (IGFBP-1) in the cells were evaluated as were the secretion levels of oestradiol, activin, progesterone, testosterone, inhibin and follistatin in cell supernatant. Results α-enolase gene silencing reduced the expression of FSHR, LHR, ERα, ERβ, GHR, and IGFBP-1 mRNA, potentiated the secretion of oestrogen, progesterone, testosterone, and follistatin of granulosa cells, and hampered the production of activin and inhibin. Conclusion ENO1 can regulate the reactivity of granulosa cells to reproductive hormones and regulate cell growth and development by adjusting their hormone secretion and reproductive hormone receptor expression. The study provided a better understanding of the functional action of ENO1 in the processes of goose ovary development and egg laying.

Male reproductive health has become a concern in public health, and semen quality is essential to male reproduction. To investigate the geographical differences in semen quality of sperm donors from the north and south of China, a total of 1012 sperm donors from all over China were enrolled in this work, which were divided by their residential latitude. There were statistically significant differences in sperm concentration among men from different latitudes in China(P=0.04). The sperm concentrations of people from 18°-27° north latitude were lower than those from 36°-45°, and 45°-54° (median 131, 134, 146, respectively, P=0.021[18°-27° vs. 36°-45°] and P=0.01[18°-27° vs. 45°-54°]). It was further confirmed when the samples were re-divided into 2 groups (typically north and south) that contains 667 samples. The analysis also showed a significant difference in terms of the regions to which the samples belonged (the median of the north is 134; the median of the south is 125; P =0.015). Although other sperm parameters don’t show significant change with latitude, some of them possess a strong relationship with sperm concentration (r=-0.19364, P

The prognostic significance of d-dimer level in patients with coronary artery disease (CAD) is not fully established. This meta-analysis aimed to examine the association between elevated d-dimer level at baseline and adverse outcomes in patients with CAD. Two independent authors comprehensively searched PubMed and Embase databases from their inception to December 31, 2020. All observational studies reporting the values of baseline d-dimer level in predicting the major adverse cardiovascular events (MACEs) or survival outcomes in patients with CAD were included. The prognostic values were calculated by pooling adjusted RR with 95% CI for the highest versus the lowest d-dimer level. Thirteen studies consisting of 25 600 patients with CAD were identified. Comparison between the highest and lowest d-dimer level showed that the pooled multivariable adjusted RR was 1.69 (95% CI, 1.53-1.86) for all-cause mortality, 2.37 (95% CI, 1.52-3.69) for cardiovascular mortality, and 1.44 (95% CI, 1.19-1.74) for MACEs, respectively. Elevated blood level of d-dimer at baseline was independently associated with higher risk of MACEs, cardiovascular death, and all-cause mortality in patients with CAD. The baseline d-dimer level may have important prognostic value in patients with CAD.

The COVID-19 pandemic, caused by SARS-CoV-2 infection, remains a dramatic threat to human life and economic well-being worldwide. Significant heterogeneity in the severity of disease was observed for patients infected with SARS-CoV-2 ranging from asymptomatic to severe cases. Moreover, male patients had a higher probability of suffering from high mortality and severe symptoms linked to cytokine storm and excessive inflammation. The NLRP3 inflammasome is presumably critical to this process. Sex differences may directly affect the activation of NLRP3 inflammasome, impacting the severity of observed COVID-19 symptoms. To elucidate the potential mechanisms underlying sex based differences in NLRP3 activation during SARS-CoV-2 infection, this review summarizes the reported mechanisms and identifies potential therapeutic targets.

Background Cyclin-dependent kinases (CDKs) are regarded as promising targets for cancer therapy. CDK2 and CDK4 are the core molecules in the G0 and G1 phases of the cell cycle. Exploring the molecular mechanism of CDK2 and CDK4 protein degradation will provide clues and solutions to control the G0 and G1 phases in tumor cells. Methods The expression levels of CDK2 and CDK4 were assessed by Western blotting and qRT-PCR. Cell viability, cell proliferation and growth were evaluated in CCK-8 and flow cytometric analysis. Protein interactions were analysed by immunoprecipitation and immunofluorescence methods. Results NVP-BEZ235 induced neuroblastoma cell arrest at the G0/G1 phase, and proliferation inhibition was associated with a significant reduction in the CDK2 and CDK4 proteins in a dose-dependent manner at nanomolar concentrations. Surprisingly, we found that the NVP-BEZ235-induced downregulation of CDK2 and CDK4 was dramatically rescued by autophagy-lysosome inhibitors. Additionally, the blockade of autophagy-related genes contributed to the remarkable rescue of CDK2 and CDK4, which thus strikingly improved NVP-BEZ235-induced G0/G1 arrest and growth inhibition of neuroblastoma cells. Subsequently, we observed the first evidence that NVP-BEZ235 induced the interaction of p62/SQSMT1 with CDK2 or CDK4 and the autophagic degradation of CDK2 and CDK4 in a cathepsin B-dependent manner. Analogous results regarding autophagy and the antiproliferative effects of NVP-BEZ235 were observed in a neuroblastoma xenograft mouse model in vivo. Conclusions These results not only established the pivotal role of the autophagy pathway in G0/G1 cell cycle-related protein turnover but also suggest the potential application of NVP-BEZ235 for cancer treatment by modulating elements of the autophagic machinery to promote degradation of G0/G1 cell cycle-related proteins.

The microbiota-gut-brain axis has emerged as a focal point of biomedical research. Alterations of gut microbiota are involved in not only various immune/inflammatory disorders but also neurological disorders including Alzheimer's disease (AD). The initial stage of the involvement of gut microbiota in the pathogenesis of AD may be the dysfunction of the blood-brain barrier (BBB). Gut microbiota-derived products in the circulation can worsen the BBB integrity, easily cross the disrupted BBB and enter the brain to promote pathological changes in AD. In this review, we first summarize the current evidence of the associations among gut microbiota, AD, and BBB integrity. We then discuss the mechanism of gut microbiota on BBB dysfunction with a focus on bacteria-derived lipopolysaccharide and exosomal high-mobility group box 1. Novel insights into the modification of the BBB as an intervention approach for AD are highlighted as well.

To evaluate the association between Chinese medicine (CM) therapy and disease-free survival (DFS) outcomes in postoperative patients with non-small cell lung cancer (NSCLC). This multiple-center prospective cohort study was conducted in 13 medical centers in China. Patients with stage I, II, or IIIA NSCLC who had undergone radical resection and received conventional postoperative treatment according to the National Comprehensive Cancer Network (NCCN) guidelines were recruited. The recruited patients were divided into a CM treatment group and a control group according to their wishes. Patients in the CM treatment group received continuous CM therapy for more than 6 months or until disease progression. Patients in the control group received CM therapy for less than 1 month. Follow-up was conducted over 3 years. The primary outcome was DFS, with recurrence/metastasis rates as a secondary outcome. Between May 2013 and August 2016, 503 patients were enrolled into the cohort; 266 were classified in the CM treatment group and 237 in the control group. Adjusting for covariates, high exposure to CM was associated with better DFS [hazard ratio (HR) = 0.417, 95% confidential interval (CI): 0.307–0.567)]. A longer duration of CM therapy (6–12 months, 12–18 months, >24 months) was associated with lower recurrence and metastasis rates (HR = 0.225, 0.119 and 0.083, respectively). In a subgroup exploratory analysis, CM therapy was also a protective factor of cancer recurrence and metastasis in both stage I–IIIA (HR=0.50, 95% CI: 0.37–0.67) and stage IIIA NSCLC postoperative patients (HR = 0.48, 95% CI: 0.33–0.71), DFS was even longer among CM treatment group patients. Longer duration of CM therapy could be considered a protective factor of cancer recurrence and metastasis. CM treatment is associated with improving survival outcomes of postoperative NSCLC patients in China. (Registration No. ChiCTR-OOC-14005398)

Background Inflammatory myofibroblastic tumor (IMT) is an indolent tumor mainly affecting children and young adults. As a rare mesenchymal tumor with unknown etiology and pathogenesis, IMT has a predilection for the lung and abdominopelvic region. Previous literature featuring IMT in the central nervous system (IMT-CNS) is rare. The clinical symptoms and radiologic features of IMT-CNS are not specific; therefore, the diagnosis is predominately based on the histopathologic and immunohistochemical analysis of the specimen. Case Description We herein present a case of a 21-year-old woman who complained of bilateral blurred vision for 15 days. Head magnetic resonance imaging demonstrated a round-shaped and irregular lesion located in the right frontal lobe. The boundary of the lesion was clear, and the lesion was homogeneously enhanced. Peripheral edema of the lesion was observed, and the mass effect was obvious. Supratentorial craniotomy tumor resection was performed. Histopathologic and immunohistochemical analysis revealed IMT, which had negative expression of anaplastic lymphoma kinase. Conclusions Remission of her symptoms was observed, and no recurrence was recorded during a 6-month follow-up.

INTRODUCTION In recent years, everolimus-eluting bioresorbable vascular scaffold stents (EE-BRS) were developed as alternative to everolimus-eluting metallic stents (EES) for coronary artery disease (CAD) treatments. Areas covered: Searches were conducted in MEDLINE, EMBASE, EBSCO, Springer, Ovid, TCTMD, Cardiosource, Clinical Trial Results and the Cochrane Library with combined key words such as bioresorbable vascular scaffold (BVS), everolimus-eluting metallic stents, EES, coronary artery disease, CAD and randomized-Controlled Trials.Finally, 5,474 patients were enrolled for comparison of device-induced thrombosis, ischemia-driven target lesion revascularization (ID-TLR), device-oriented composite endpoints (DOCE), patient-oriented composite endpoints (POCE), and target vessel failure (TVF) between EE-BRS and EES treatments. The primary literature search retrieved 200 records. Expert Opinion: There was no difference regarding DOCEs, POCEs and ID-TLRs for 1 or 2 years, whereas there were significant differences regarding thrombosis between EE-BRS and EES interventions in the 1-year (pooled HR, 2.15, 95%CI: 1.11, 4.18) and 2-year follow-ups (pooled HR, 2.02, 95%CI: 1.08, 3.78), but not in the 3-year follow-up (pooled HR, 1.57, 95%CI: 0.66, 3.75) anymore. The results of this study showed no inferiority of EE-BRS regarding TVF, DOCE, POCE and ID-TLR 1-year and 2-years after interventions, but enhanced risk of thrombosis in the EE-BRS patients, which disappeared in 3-year follow-ups.

Background Oxidative stress is an important pathogenic factor in influenza A virus infection. It has been found that reactive oxygen species induced by the H9N2 influenza virus is associated with viral replication. However, the mechanisms involved remain to be elucidated. Methods In this study, the role of autophagy was investigated in H9N2 influenza virus-induced oxidative stress and viral replication in A549 cells. Autophagy induced by H9N2 was inhibited by an autophagy inhibitor or RNA interference, the autophagy level, viral replication and the presence of oxidative stress were detected by western blot, TCID50 assay, and Real-time PCR. Then autophagy and oxidative stress were regulated, and viral replication was determined. At last, the Akt/TSC2/mTOR signaling pathways was detected by western blot. Results Autophagy was induced by the H9N2 influenza virus and the inhibition of autophagy reduced the viral titer and the expression of nucleoprotein and matrix protein. The blockage of autophagy suppressed the H9N2 virus-induced increase in the presence of oxidative stress, as evidenced by decreased reactive oxygen species production and malonaldehyde generation, and increased superoxide dismutase 1 levels. The changes in the viral titer and NP mRNA level caused by the antioxidant, N-acetyl-cysteine (NAC), and the oxidizing agent, H2O2, confirmed the involvement of oxidative stress in the control of viral replication. NAC plus transfection with Atg5 siRNA significantly reduced the viral titer and oxidative stress compared with NAC treatment alone, which confirmed that autophagy was involved in the replication of H9N2 influenza virus by regulating oxidative stress. Our data also revealed that autophagy was induced by the H9N2 influenza virus through the Akt/TSC2/mTOR pathway. The activation of Akt or the inhibition of TSC2 suppressed the H9N2 virus-induced increase in the level of LC3-II, restored the decrease in the expression of phospho-pAkt, phospho-mTOR and phospho-pS6 caused by H9N2 infection, suppressed the H9N2-induced increase in the presence of oxidative stress, and resulted in a decrease in the viral titer. Conclusion Autophagy is involved in H9N2 virus replication by regulating oxidative stress via the Akt/TSC2/mTOR signaling pathway. Thus, autophagy maybe a target which may be used to improve antiviral therapeutics.

Introduction: Inflammatory reactions, including those mediated by the NLRP3 inflammasome, maintain the body's homeostasis by removing pathogens, repairing damaged tissues, and adapting to stressed environments. However, uncontrolled activation of the NLRP3 inflammasome tends to cause various diseases using different mechanisms. Recently, many inhibitors of the NLRP3 inflammasome have been reported and many are being developed. In order to assess their efficacy, specificity, and mechanism of action, the screening process of inhibitors requires various types of cell and animal models of NLRP3-associated diseases.Areas covered: In the following review, the authors give an overview of the cell and animal models that have been used during the research and development of various inhibitors of the NLRP3 inflammasome.Expert opinion: There are many NLRP3 inflammasome inhibitors, but most of the inhibitors have poor specificity and often influence other inflammatory pathways. The potential risk for cross-reaction is high; therefore, the development of highly specific inhibitors is essential. The selection of appropriate cell and animal models, and combined use of different models for the evaluation of these inhibitors can help to clarify the target specificity and therapeutic effects, which is beneficial for the development and application of drugs targeting the NLRP3 inflammasome.

Introduction: Up to 30% of patients with Guillain-Barre syndrome (GBS) develop respiratory failure requiring intensive care unit (ICU) admission and mechanical ventilation. Progressive weakness of the respiratory muscles is the leading cause of acute respiratory distress and respiratory failure with hypoxia and/or hypercarbia. Bulbar weakness may compromise airway patency and predispose patients to aspiration pneumonia. Areas covered: Clinical questions related to the use of mechanical ventilation include but are not limited to: When to start? Invasive or noninvasive? When to wean from mechanical ventilation? When to perform tracheostomy? How to manage complications of GBS in the ICU including nosocomial infection, ventilator-associated pneumonia, and ICU-acquired weakness? In this narrative review, the authors summarize the up-to-date knowledge of the incidence, pathophysiology, evaluation, and general management of respiratory failure in GBS. Expert opinion: Respiratory failure in GBS merits more attention from caregivers. Emergency intubation may lead to life-threatening complications. Appropriate methods and time point of intubation and weaning, an early tracheostomy, and predictive prophylaxis of complications benefit patients' long-term prognosis.

Guillain–Barré syndrome (GBS) is an acute polyneuropathy mostly characterized by acute flaccid paralysis with or without sensory/autonomous nerve dysfunction. Current immuno therapies including intravenous immunoglobulin (IVIg), plasma exchange (PE), and newly developed biological drugs benefit patients by alleviating hyperreactive immune responses. Up to 30% of patients develop respiratory failure during hospitalization and require mechanical ventilation and intensive care. Immunotherapies, mechanical ventilation, supportive care, and complication management during the intensive care unit (ICU) stay are equally emphasized. The most important aspect of intensive care and treatment of severe GBS, that is, mechanical ventilation, has been extensively reviewed elsewhere. In contrast to immunotherapies, care and treatment of GBS in the ICU setting are largely empirical. In this review, we intend to stress the importance of intensive care and treatment, other than mechanical ventilation in patients with severe GBS. We summarize the up-to-date knowledge of pharmacological therapies and ICU management of patients with severe GBS. We aim to answer some key clinical questions related to the management of severe GBS patients including but not limited to: Is IVIg better than PE or vice versa? Whether combinations of immune therapies benefit more? How about the emerging therapies promising for GBS? When to perform tracheal intubation or tracheostomy? How to provide multidisciplinary supportive care for severe cases? How to avert life-threatening complications in severe cases?

Background: Galectin-3 may predict mortality for patients with aortic stenosis (AS) after transcatheter aortic valve replacement (TAVR). However, the results were inconsistent. We aimed to evaluate the association between baseline galectin and mortality after TAVR in a meta-analysis. Methods: Related follow-up studies were obtained by systematic search of PubMed, Cochrane’s Library, and Embase databases. Both the fixed- and the random-effect models were used for the meta-analysis. Subgroup analyses were performed to evaluate the influences of study characteristics on the outcome. Results: Five prospective cohort studies with 854 patients were included, with a follow-up period between 1 and 1.9 years. Patients with higher baseline circulating galectin-3 had an increased risk of all-cause mortality after TAVR (random-effects model: risk ratio [RR]: 1.63, 95% confidence interval [CI]: 1.19–2.23, P=0.002; fixed-effects model: RR: 1.62, 95% CI: 1.19–2.20, P=0.002; I2 = 4%). Adjustment of estimated glomerular filtration rate (RR: 1.73, P=0.02) or B-type natriuretic peptide (BNP) or N-terminal pro-BNP (RR: 1.83, P=0.02) did not significantly affect the result. A trend of stronger association between higher baseline circulating galectin-3 and increased risk of all-cause mortality after TAVR was observed in studies with an enzyme-linked fluorescent assay (ELFA) (RR: 3.04, P=0.003) compared with those with an enzyme-linked immunosorbent assay (ELISA) (RR: 1.42, P=0.04; P for subgroup difference =0.06). Conclusion: Higher circulating galectin-3 before the procedure may predict all-cause mortality of AS patients after TAVR.

Background: Resistant starch type 2 (RS2) has been documented to regulate gut microbiota and to improve the clinical outcomes of several diseases. However, whether RS2 may benefit patients with end-stage renal disease under maintenance hemodialysis (MHD) remains unknown. Methods: We conducted a systemic review and meta-analysis of randomized controlled trials (RCTs). Adult patients receiving MHD were treated with RS2 (CRD42020160332). The primary outcomes were changes of uremic toxins, and the secondary outcomes were changes of inflammatory indicators, albumin and phosphorus. Results: After screening 65 records, five RCTs (n = 179) were included. A significant decrease of blood urea nitrogen (weighted mean difference (WMD) = -6.91, 95% CI: -11.87 to -1.95, I2 = 0%, P = 0.006), serum creatinine (WMD = -1.11, 95% CI: -2.18 to -0.05, I2 = 44%, P = 0.04) and interleukin (IL)-6 in blood (standard mean difference (SMD) = -1.08, 95% CI: -1.64 to -0.53, I2 = 35%, P = 0.0001) was revealed in the RS2 group. Analyses of blood levels of uric acid, p-cresyl sulfate, indoxyl sulfate, high sensitive C-reaction protein, albumin and phosphorus yielded no significant difference. Conclusions: Our results suggest that RS2 may improve the residual renal function of patients under MHD and mitigate a proinflammatory response.

Several severity scales have been documented to predict the short-term mortality of septic patients. However, the predictive efficacies of different severity scales in the long-term mortality of the elderly have yet to be evaluated.In the retrospective study, a cohort of 4,370 elderly (≥65 years) septic patients admitted to the intensive care unit (ICU) were divided into three different age groups, i.e., the younger-old group (65 years ≤ age75 years), the older-old group (75 years ≤ age85 years) and the oldest-old group (age ≥85 years). Five scales, including the Simplified Acute Physiology Score II (SAPS II), the Oxford Acute Severity of Illness Score (OASIS), the Modified Logistic Organ Dysfunction System (MLODS), the Systemic Inflammatory Response Syndrome (SIRS) and Sequential Organ Failure Assessment (SOFA), were used for disease severity evaluations. The Kaplan-Meier survival curve, and the area under the receiver operating characteristic curve (AUC) were used to assess prognostic values of the long-term mortality of each severity scale.Compared with patients in the oldest-old group, those in the younger-old and the older-old groups had higher scores of SAPS II and OASIS, indicating more serious illness and worse prognosis. The survival time of patients was inversely related to age; the mean survival time was the longest in the youngerold group, followed by the older-old group and the oldest-old group. SAPS II had the best prognostic value (AUC: 0.648 for SAPS II, 0.579 for MLODS, 0.577 for SOFA, 0.612 for OASIS and 0.515 for SIRS, P0.01) for the 4-year all-cause mortality. Elderly patients with an SAPS II score43 had a lower survival rate regardless of age.The long-term mortality of elderly patients with sepsis is increased with age. SAPS II can better predict the long-term prognosis of elderly septic patients in ICU.

Hypertensive encephalopathy (HE) is a subset of posterior reversible encephalopathy syndrome. It typically involves the posterior supratentorial structures, but variations do occur. However, isolated brainstem involvement in HE is rare, with a few cases reported in the literature. Herein, we report a case of acute hypertensive brainstem encephalopathy in which the patient had mild symptoms with very high blood pressure and normal neurological examination. The computed tomography of the brain showed diffuse hypodensity at brainstem. The patient's symptoms improved drastically after hypertension had been controlled. Marked clinical-radiologic dissociation in this particular case was highly suggestive of hypertensive brainstem encephalopathy. Prompt recognition of the condition and aggressive treatment of hypertension in such patients is crucial to relieve oedema and to prevent life-threatening progression. Nevertheless, there is still a lack of awareness among physicians and radiologists regarding this rare clinical entity.

IntroductionThe aim was to observe the effect of Toll-like receptor 4 (TLR4) deficiency on clinical severity and expression of Th1/Th2/Th17-associated cytokines in experimental autoimmune neuritis (EAN).Material and methodsWe selected C57BL/10 wild type (WT) mice and TLR4 knockout (KO) mice with the C57BL/10 background for induction of the EAN model by immunizing mice twice (days 0 and 8) via subcutaneous injection of 180 µg P0 peptide 180–199 emulsion in 25 µl of PBS and 0.5 mg Mycobacterium tuberculosis (Difco, USA) in 25 µl of Freund’s incomplete adjuvant into the back of mice. The concentrations of serum cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ and TNF) were determined using the Ms Th1/Th2/Th17 CBA kit.ResultsWe found that TLR4 deficiency could attenuate the clinical severity and delay the onset of EAN. Moreover, our data showed that the sera levels of IFN-γ, TNF, IL-6 and IL-17A were elevated in the WT mice with EAN when compared with the naive WT mice, but only the production of IL-17A was significantly lower in the TLR4 KO mice with EAN than in their WT counterparts.ConclusionsBased on these findings, TLR4 may contribute to the pathogenesis of EAN by regulating Th17 cells and the production of Th17-associated factors. However, the exact mechanism remains unclear and more evidence is needed to elucidate its role in EAN.

The aim of our study was to compare the sperm retrieval rates (SRRs) and clinical outcomes of patients with different causes of azoospermia who underwent microdissection testicular sperm extraction-intracytoplasmic sperm injection (micro-TESE-ICSI). We conducted a retrospective study at the Reproductive Medicine Center of Peking University Third Hospital in Beijing, China, from January 2014 to December 2017. This study examined 769 patients with nonobstructive azoospermia who underwent 347 cycles of micro-TESE-ICSI. Patients with azoospermia were classified into Group A (Klinefelter syndrome, n = 284, 125 cycles), Group B (azoospermia Y chromosome factor c [AZFc] microdeletion, n = 91, 64 cycles), Group C (cryptorchidism, n = 52, 39 cycles), Group D (previous mumps and bilateral orchitis, n = 23, 23 cycles), and Group E (idiopathic azoospermia, n = 319, 96 cycles). Clinical characteristics, SRR, embryonic development, and pregnancy outcomes of the patients were compared between all groups. Patients in Group D had the highest and most successful SRR. The average SRR for all patients was 46.0%. The rates of clinical pregnancy, implantation, and live birth in Group D were 78.3%, 65.0%, and 74.0%, respectively, which were higher than those in all other groups (P < 0.05). Group B patients had the lowest clinical pregnancy, implantation, and live birth rates of all groups (P < 0.05). No differences were found in the miscarriage rate or birth defects among the groups (P > 0.05). Patients with orchitis had the highest SRR and best clinical outcomes. Although AZFc microdeletion patients had a higher SRR, their clinical outcomes were worse.

Acute kidney injury (AKI) is a serious complication in the intensive care unit (ICU), which may increase the mortality of critically ill patients. The red blood cell distribution width (RDW) has proved useful as a predictor of short-term prognosis in critically ill patients with AKI. However, it remains unknown whether RDW has a prognostic value of long-term all-cause mortality in these patients. The data of 18279 critically ill patients with AKI at first-time hospital admission were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database. The tertiles of the RDW values were used to divide subjects into three groups, namely RDW

BACKGROUND: Renal anemia is a severe complication of chronic kidney disease (CKD) and may worsen its prognosis. Roxadustat is the only oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that has been proved effective to treat renal anemia. However, effects of roxadustat on non-dialysis-dependent CKD (NDD-CKD) have yet to be supported by evidence-based medicine. METHODS: Based on the databases of PubMed, EMBASE and Web of Science by 12 April 2019 (CRD42019133225), a meta-analysis of randomized controlled trials (RCTs) on roxadustat for treatment of NDD-CKD was conducted. Primary outcomes were parameters of hemoglobin (Hb) and Hb response. Secondary outcomes were hepcidin, ferritin, total iron binding capacity (TIBC), transferrin saturation (TAST), incidences of diarrhea, adverse events (AEs) and severe adverse events (SAEs). The risk of bias and the quality of evidence were assessed, respectively. Both continuous and binary variables were analyzed by the random effects models. Sensitivity analyses were performed when a significant heterogeneity was observed (P50%). RESULTS: Finally, three studies with a total of 214 subjects in the roxadustat group and 80 subjects in the placebo group were enrolled. An increase of Hb [weighted mean difference (WMD) =1.22, 95% CI: 0.95 to 1.49, P

Mounting evidence suggests that neuroinflammation is not just a consequence but a vital contributor to the development and progression of Parkinson’s disease (PD). Microglia in particular, may contribute to the induction and modulation of inflammation in PD. Upon stimulation, microglia convert into activated phenotypes, which exist along a dynamic continuum and bear different immune properties depending on the disease stage and severity. Activated microglia release various factors involved in neuroinflammation, such as cytokines, chemokines, growth factors, reactive oxygen species (ROS), reactive nitrogen species (RNS), and prostaglandins (PGs). Further, activated microglia interact with other cell types (e.g., neurons, astrocytes and mast cells) and are closely associated with α-synuclein (α-syn) pathophysiology and iron homeostasis disturbance. Taken together, microglial activation and microglia-mediated inflammatory responses play essential roles in the pathogenesis of PD and elucidation of the complexity and imbalance of microglial activation may shed light on novel therapeutic approaches for PD.

Macrophage migration inhibitory factor (MIF) plays an important role in the pathogenesis of Guillain-Barré syndrome (GBS) and its animal model experimental autoimmune neuritis (EAN), which may offer an opportunity for the development of the novel therapeutic strategies for GBS. Areas covered: 'macrophage migration inhibitory factor' and 'Guillain-Barré syndrome' were used as keywords to search for related publications on Pub-Med, National Center for Biotechnology Information (NCBI), USA. MIF is involved in the etiology of various inflammatory and autoimmune disorders. However, the roles of MIF in GBS and EAN have not been summarized in the publications we identified. Therefore, in this review, we described and analyzed the major roles of MIF in GBS/EAN. Primarily, this molecule aggravates the inflammatory responses in this disorder. However, multiple studies indicated a protective role of MIF in GBS. The potential of MIF as a therapeutic target in GBS has been recently demonstrated in experimental and clinical studies, although clinical trials have been unavailable to date. Expert opinion: MIF plays a critical role in the initiation and progression of GBS and EAN, and it may represent a potential therapeutic target for GBS.

To evaluate and compare left and right testicular tissue histopathology and Johnsen score, and to investigate the necessity for bilateral testicular biopsy. We recruited180 patients with non-obstructiveazoospermia (NOA) on testicular biopsy who had undergonetesticular sperm aspiration (TESA). Pathological sections of testicular tissue were diagnosed by specially-assigned doctors, who evaluated pathological findings, determined the Johnsen score and confirmed for the presence or absence of sperm. Sperm positive rates for left and right testicular histopathology were 55.0% and 51.7% respectively, and the proportion of Johnsen scores≥8 for left and right testes were 53.3% and 50.0%, respectively. Cohen kappa values revealed that the identification of sperm in bilateral testicular samples was not consistent and was related to random effects; Optimized cut-off value for bilateral testicular volume was 11ml (Johnsen score ≥8), and optimized cut-off values of E2 on left and right testes were 144.5pmol/L and 133.5 pmol/L (Johnsen score≤7). However, age, serum prolactin (PRL), follicle stimulating hormone (FSH), luteinizing hormone (LH) and total testosterone (TT) levels were not accurate predictors for the existence of testicular sperm. There was nostatistical significance between left and right testicular histopathology in terms of sperm positive rates or Johnsen score; the Johnsen score were caused entirely by random effects and a score from one side could not represent the other side. Therefore, we recommend that both testes need to undergo surgery when NOA patients undergo testicular biopsy or sperm retrieval.

We aim to identify the key protein interaction networks and implicated pathways of BK virus nephropathy (BKVN) via bioinformatic methods. The microarray data GSE75693 of 30 patients with stable kidney transplantation and 15 with BKVN were downloaded and analyzed by using the limma package to identify differentially expressed genes (DEGs). Then the gene ontology (GO) functional enrichment analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were done to investigate the molecular function (MF), biological process (BP), cellular components (CC) and pathways of DEGs. Finally, protein-protein interactions (PPIs) were constructed, and the hub proteins were identified. As a result, 249 up-regulated genes and 253 down-regulated genes of BKVN patients were selected based on criteria of P > 0.01 and fold change >2.0. GO and KEGG showed that DEGs were mainly located in nucleus and cytosol, and were implicated in the immune responses. In the PPI analysis, 26 up-regulated and 8 down-regulated proteins composed the pivotal interaction network. CXCL10, EGF and STAT1 were identified as hub proteins in BKVN. In conclusion, CXCL10, EGF and STAT1 may induce kidney injuries by promoting inflammation and prohibiting reparation of tissue damage in BKVN.

Background/Aims: Dysbiosis of the intestinal microbiota may accelerate the progression of chronic kidney disease (CKD) by increasing the levels of urea toxins. In recent years, probiotics have been recognized to maintain the physiological balance of the intestinal microbiota. In this study, we aim to assess the therapeutic effects of probiotics on CKD patients with and without dialysis via meta-analysis. Methods: We conducted a meta-analysis of randomized controlled trials (RCTs) by searching the databases of Pubmed, EMBASE and Cochrane Library (No. CRD42018093080). Studies on probiotics for treatment of CKD adults lasting for at least 4 weeks were selected. The primary outcomes were the levels of urea toxins, and the second outcomes were the levels of interleukin (IL)-6, C-reactive protein (CRP) and hemoglobin (Hb). The risk of bias was assessed by Cochrane Collaboration’ tool, and the quality of evidence was appraised with the Grading of Recommendation Assessment. Means and standard deviations were analyzed by random effects analysis. Stratified analysis was done and sensitivity analysis was performed when appropriate. Results: Totally, eight studies with 261 patients at CKD stage 3 to 5 with and without dialysis were included. We found a decrease of p-cresyl sulfate (PCS) of 3 studies with 125 subjects (P = 0.01, SMD -0.57, 95% CI, -0.99 to -0.14, I2 = 25%) and an increase of IL-6 in 3 studies with 134 subjects (P = 0.03, 95% CI, SMD 0.37, 0.03 to 0.72, I2 = 0%) in the probiotics groups. Analysis of serum creatinine (P = 0.47), blood urine nitrogen (P = 0.73), CRP (P = 0.55) and Hb (P = 0.49) yielded insignificant difference. Conclusion: Limited number of studies and small sample size are limitations of our study. Probiotics supplementation may reduce the levels of PCS and elevate the levels of IL-6 whereby protecting the intestinal epithelial barrier of patients with CKD.

Background It remains an urgent need for early recognition of disease severity, treatment option and outcome of Guillain-Barré syndrome (GBS). The chief complaint may be quickly obtained in clinic and is one of the candidates for early predictors. However, studies on the chief complaint are still lacking in GBS. The aim of the study is to describe the components of chief complaints of GBS patients, and to explore association between chief complaints and disease severity/treatment option/outcome of GBS, so as to aid the early prediction of the disease course and to assist the clinicians to prescribe an optimal early treatment. Methods A total of 523 GBS patients admitted to the First Hospital of Jilin University from 2003 to 2013 were enrolled for retrospective analysis. The data of chief complaints, clinical manifestations, and treatment options, etc. were collected. The clinical severity was evaluated by the Medical Research Council sum score and the Hughes Functional Grading Scale. The prognosis at 6 month after discharge was described by modified Erasmus GBS outcome score. The clinic GBS severity evaluation scale (CGSES), a newly established model in our study, was used to explore the role of chief complaints to predict intravenous immunoglobulin (IVIg). Results The major components of the chief complaints of GBS patients were weakness, numbness, pain, cranial nerve involvement, dyspnea, ataxia and autonomic dysfunction. Chief complaint of weakness was a predictor of severe disease course and poor short-term outcome, while chief complaint of numbness and cranial nerve involvement were promising predictors. Cranial nerve involvement was the predictor of ventilator dependence. The percentages of 366 GBS patients, who need IVIg treatment at nadir with CGSES ranging from 1 to 4, were 50.00, 67.34, 80.61, and 90.67%, respectively. Conclusions Chief complaints are clinic predictors of disease severity, ventilator dependence and short-term outcome. IVIg treatment during hospitalisation could be predicted in clinic using CGSES score.

// Ying Wang 1 , Wenjuan Lang 1 , Yaqian Zhang 1 , Xiaoyi Ma 2 , Chunkui Zhou 1 and Hong-Liang Zhang 1,3 1 Department of Neurology, The First Hospital of Jilin University, Changchun, China 2 Department of Neurology, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China 3 Department of Life Sciences, The National Natural Science Foundation of China, Beijing, China Correspondence to: Ying Wang, email: // Chunkui Zhou, email: // Hong-Liang Zhang, email: // Keywords : Guillain-Barre syndrome, long-term prognosis, predictors, self-limitation, intravenous immunoglobulin Received : July 12, 2017 Accepted : August 17, 2017 Published : September 01, 2017 Abstract Background: The long-term follow-up system for Guillain-Barre syndrome (GBS) is not well established worldwide. In our study, the preliminary data of the long-term prognosis of GBS are collected to explore the prognosis of GBS and the effect of intravenous immunoglobulin (IVIg) treatment. Methods: The follow-up data of 186 patients with GBS admitted from 2003 to 2013 were collected in 2015 via phone interview. The GBS disability scale score was ranked by clinician to evaluate the long-term prognosis. The clinical data during the acute phase were also collected. Results: The mortality rates were 2.15%, 5.45% and 7.89% at discharge, 2-5 years and 6-10 years after disease, respectively. The GBS disability scale score improved dramatically from discharge to 2-12 years after the acute phase. The self-limitation, the spontaneous recovery of disease, occurred both at acute phase and 2-5 years after discharge. Comparisons between IVIg-treated patients and GBS patients who only received supportive care revealed no significant difference of long-term prognosis. Conclusion: The long-term prognosis of GBS appears not to be influenced by treatment options. The long-term improvement of IVIg treated-patients might be due to the self-limitation of GBS per se instead of the IVIg treatment.

Although ATRA is involved in regulating the proliferation and differentiation of chondrocytes, its underlying mechanism remains unknown. Here we showed that ATRA could stimulate the proliferation of antler chondrocytes and expression of COL X and MMP13 which were two well-known markers for hypertrophic chondrocytes. Silencing of CRABP2 prevented the induction of ATRA on chondrocyte terminal differentiation, while overexpression of CRABP2 exhibited the opposite effects. CYP26A1 and CYP26B1 weakened the sensitivity of antler chondrocytes to ATRA. Further analysis evidenced that ATRA might induce chondrocyte terminal differentiation and modulate the expression of BMP2, WNT4, and RUNX1 through RARα/RXRα. Knockdown of BMP2 enhanced the induction of ATRA on the expression of COL X and MMP13, whereas overexpression of BMP2 abrogated this effectiveness. WNT4 might mediate the effects of ATRA and BMP2 on chondrocyte terminal differentiation. Dysregulation of BMP2 impaired the regulation of ATRA on WNT4 expression. Administration of ATRA to antler chondrocytes transfected with RUNX1 siRNA failed to induce the differentiation. Conversely, rRUNX1 strengthened the stimulation of ATRA on the expression of COL X and MMP13. Simultaneously, RUNX1 was a downstream effector of BMP2 and WNT4 in chondrocyte terminal differentiation. Moreover, WNT4 might play an important role in the crosstalk between BMP2 and RUNX1. Attenuation of BMP2 or WNT4 enhanced the interaction between ATRA and RUNX1, while constitutive expression of BMP2 or WNT4 reversed the regulation of ATRA on RUNX1. Collectively, WNT4 may act downstream of BMP2 to mediate the effects of ATRA on the terminal differentiation of antler chondrocytes through targeting RUNX1.

Objective: To present our treatment experiences and the follow-up data of patients with paradoxical embolism (PDE). Methods: The clinical characteristics, management, and follow-up data of all included patients who were diagnosed with PDE at Fuwai Hospital from January 1994 to October 2015 were recorded. Results: Twelve patients were included; all had a pulmonary embolism, and 8 had deep venous thrombosis. The artery embolisms involved the cerebral artery (7 patients), renal artery (2 patients), mesentery artery (2 patients), popliteal artery (1 patient), descending aorta thrombus (1 patient), and thrombus-straddled patent foramen ovale (PFO) (1 patient). PFO was found in 3 cases. One patient underwent thrombectomy and PFO closure; Six patients received thrombolysis; and 3 patients were implanted with a vena cava filter. Long-term anticoagulation with warfarin was recommended for each patient. One patient died from ventricular fibrillation despite cardiopulmonary resuscitation. Eleven patients were discharged with improvements. No late mortality occurred in 8 patients with a complete follow-up of 10.6â17.7 years. One had a recurrent deep venous thrombosis. No patient had a recurrent pulmonary or arterial embolism. Two patients changed their treatment from warfarin to aspirin; others remained on warfarin. Only 1 case had an occasional gum bleeding. Conclusions: PDE treatment including thrombolysis, anticoagulation, and embolectomy should be individualized. We recommend long-term anticoagulation therapy to prevent the recurrence of PDE, especially to those with an intracardiac communication or persistent risk factors for re-thrombosis. Keywords: Paradoxical embolism, Pulmonary embolism, Deep venous thrombosis, Patent foramen ovale

The cartilage vascularization and chondrocyte survival are essential for endochondral ossification which occurs in the process of antler growth. Angiopoietins (Ang) is a family of major angiogenic growth factors and involved in regulating the vascularization. However, the expression and regulation of Angs in the antler are still unknown. The aim of this study is to localize the expression of Ang-1, Ang-2 and their receptor Tie-2 in sika deer antler using in situ hybridization and focused on analyzing the regulation of testosterone, estrogen, all-trans-retinoic acid (ATRA) and 9cRA on their expression in antler chondrocytes. The results showed that Ang-1, Ang-2 and Tie-2 were highly expressed in antler chondrocytes. Administration of testosterone to antler chondrocytes led to a notable increase in the expression of Ang-1 and Tie-2, and a reduction in the expression of Ang-2. The similar result was also observed after estrogen treatment. In contrast, ATRA and 9cRA could inhibit the expression of Ang-1 in antler chondrocytes and heighten the expression of Ang-2. Simultaneously, ATRA could downregulate the expression of Tie-2 in antler chondrocytes at 12 and 24 h, while 9cRA upregulate the expression of Tie-2 at 3 and 6 h. Collectively, Ang-1, Ang-2 and Tie-2 are expressed in antler chondrocytes and their expression can be affected by testosterone, estrogen, ATRA and 9cRA.

Although Gja1 has been proved to play an important role in uterine decidualization, its regulatory mechanism remains largely unknown. Here, we showed that Gja1 was highly expressed in the decidual cells and promoted the proliferation of uterine stromal cells and expression of Prl8a2 and Prl3c1, which were two well-known differentiation markers for decidualization. Further analysis revealed that Gja1 might act downstream of Acvr1 and cAMP to regulate the differentiation of uterine stromal cells. Administration of cAMP analog 8-Br-cAMP to Acvr1 siRNA-transfected stromal cells resulted in an obvious increase of Gja1 expression, whereas PKA inhibitor H89 impeded the induction of Gja1 elicited by Acvr1 overexpression, indicating that cAMP–PKA signal mediates the regulation of Acvr1 on Gja1 expression. In uterine stromal cells, knockdown of Gja1 blocked the cAMP induction of Hand2. Moreover, siRNA-mediated downregulation of Hand2 impaired the stimulatory effects of Gja1 overexpression on the expression of Prl8a2 and Prl3c1, whereas constitutive expression of Hand2 reversed the inhibitory effects of Gja1 siRNA on stromal differentiation. Meanwhile, Gja1 might play a vital role in the crosstalk between Acvr1 and Hand2. Collectively, Gja1 may act downstream of cAMP–PKA signal to mediate the effects of Acvr1 on the differentiation of uterine stromal cells through targeting Hand2.

Acrolein has been reported to have diverse toxic effects on various organs, including the reproductive system. However, little is known regarding the effects of maternal acrolein exposure on testicular steroidogenesis in male offspring. The present study investigated the effects of acrolein on fetal testosterone production and associated genes. Pregnant Sprague‑Dawley rats were intraperitoneally injected with vehicle (normal saline) or 1, 2 or 5 mg/kg acrolein from gestational day (GD) 14‑20, and fetal testes were examined on GD 21. Fetal body and testicular weights were markedly reduced in pups following exposure to high doses of acrolein (5 mg/kg) in late pregnancy. Notably, in utero exposure of 5 mg/kg acrolein significantly decreased the testicular testosterone level and downregulated the expression levels of steroidogenic acute regulatory protein (StAR) and 3β‑hydroxysteroid dehydrogenase (3β‑HSD), whereas the levels of other steroidogenic enzymes, including scavenger receptor class B, cholesterol side‑chain cleavage enzyme and steroid 17 alpha‑hydroxylase/17,20 lyase, were unaffected. Furthermore, the 3β‑HSD immunoreactive area in the interstitial region of the fetal testes was reduced at a 5 mg/kg dose, whereas the protein expression levels of 4‑hydroxynonenalwere dose‑dependently increased following maternal exposure to acrolein. mRNA expression levels of insulin‑like factor 3, a critical gene involved in testicular descent, were unaltered following maternal acrolein exposure. Taken together, the results of the present study suggested that maternal exposure to high doses of acrolein inhibited fetal testosterone synthesis, and abnormal expression of StAR and 3β‑HSD may be associated with impairment of the steroidogenic capacity.

Although 13cRA is involved in the regulation of cellular proliferation and differentiation, its physiological roles in chondrocyte proliferation and differentiation still remain unknown. Here, we showed that 13cRA could induce the proliferation of sika deer antler chondrocytes and expression of Ccnd3 and Cdk6. Administration of 13cRA to antler chondrocytes resulted in an obvious increase in the expression of chondrocyte marker Col II and hypertrophic chondrocyte marker Col X. Silencing of Crabp2 expression by specific siRNA could prevent the 13cRA-induced up-regulation of Col X, whereas overexpression of Crabp2 showed the opposite effects. Further study found that Crabp2 mediated the regulation of 13cRA on the expression of Runx3 which was highly expressed in the antler cartilage and inhibited the differentiation of antler chondrocytes. Moreover, attenuation of Runx3 expression greatly raised 13cRA-induced chondrocyte differentiation. Simultaneously, 13cRA could stimulate the expression of Cyp26a1 and Cyp26b1 in the antler chondrocytes. Inhibition of Cyp26a1 and/or Cyp26b1 reinforced the effects of 13cRA on the expression of Col X and Runx3, while overexpression of Cyp26b1 rendered the antler chondrocytes hyposensitive to 13cRA. Collectively, 13cRA may play an important role in the differentiation of antler chondrocytes through targeting Runx3. Crabp2 enhances the effects of 13cRA on chondrocyte differentiation, while Cyp26a1 and Cyp26b1 weaken the sensitivity of antler chondrocytes to 13cRA.