Follicle Stimulating Hormone Inhibits the Expression of p53 Up-Regulated Modulator of Apoptosis Induced by Reactive Oxygen Species Through PI3K/Akt in Mouse Granulosa Cells.

In mammalian ovaries, follicular atresia occurs periodically and destroys almost all the follicles in the ovary. Follicle-stimulating hormone (FSH) acts as the primary survival factor during follicular atresia by preventing apoptosis in granulosa cells (GCs). Many studies have demonstrated that oxidative stress-induced apoptosis is a main cause of follicular atresia. Reactive oxygen species (ROS)-induced GCs apoptosis is regulated by a variety of signaling pathways involving numerous genes and transcription factors. Therefore, we examined whether FSH inhibits the expression of p53 up-regulated modulator of apoptosis (PUMA) induced by reactive oxygen species (ROS) through phosphoinositide 3-kinase (PI3K) / protein kinase B (AKT) in mouse GCs. In vivo study: thirty-two-mice were randomly assigned to four groups and given FSH. We found that FSH can inhibit the 3-nitropropionic acid (3-NP) induced apoptosis and PUMA expression in mRNA level. Moreover, In vitro experiment, we found that FSH can inhibit the H(2)O(2)-induced apoptosis and PUMA expression in mRNA level. Additionally, we also found that PI3K/AKT inhibitor LY294002 abolished the downregulation of PUMA mRNA by FSH in vitro, In conclusion, FSH inhibit the expression of PUMA induced by ROS through PI3K/AKT pathway in vivo and vitro.

[Prevention and treatment of bearing dislocation of mobile-bearing unicompartmental knee arthroplasty].

Bearing dislocation is a special complication of mobile-bearing unicompartmental arthroplasty, caused by many factors, such as imbalance of the flexion and extension gap, malposition of components, impingement by the remaining osteophytes and cement, damage or delayed chronic laxity of medial collateral ligament, traumatic accident and habitual high knee flexion. It can be reduced by strictly controlling the operation indications before operation, osteotomy and implanting the prosthesis accurately while protecting the medial collateral ligament during operation, actively guiding the appropriate rehabilitation actions and activity intensity of patients after operation. Treatment should be individualized according to the causes and individual conditions of patients.

[Comparison of the early efficacy of unicompartmental and total knee arthroplasty in patients with medial compartmental osteoarthritis of the knee: a propensity score matching study].

Objective: To compare the short-term efficacy of unicompartmental knee arthroplasty (UKA) and total knee arthroplasty(TKA) in the treatment of medial compartmental knee osteoarthritis. Methods: A retrospective analysis was performed on 197 patients with medial compartment osteoarthritis of the knee treated by the same group of doctors from January 2015 to December 2018.There were 86 males and 111 females, aged (67.7±10.5) years (range: 46 to 92 years), among which 101 cases received UKA and 96 cases received TKA.The UKA and TKA patients were matched by the propensity score matching method, and a total of 41 pairs of patients were successfully matched.The difference of short-term outcomes between the two groups were compared by t test, χ(2) test or Fisher exact probability methods. Results: Compared with TKA group, the postoperative reduction of hemogloblin in the UKA group was lower ((15.3±6.4) g/L vs. (20.1±7.5) g/L, t=-3.117, P<0.01), opioid dosage was lower ((160.5±29.3) mg vs. (186.1±46.8) mg, t=-2.969, P<0.01), and the length of hospital stay was shorter ((7.0±2.0)d vs. (10.0±2.5)d, t=-6.000, P<0.01). Forgotten joint score of UKA group was higher ( (65.1±7.6) vs. (58.3±13.9) , t=2.732, P<0.01), the incidence of knee clunk or crepitus was lower (P=0.03) . There was no significant difference in the time of surgical tourniquet, range of motion, American knee society clinical score and incidence of deep vein thrombosis in lower extremities between the two groups.No complications such as surgical site infection, prosthesis loosening and dislocation occurred in the two groups. Conclusion: The early effect of UKA is similar to that of TKA, and it is better than TKA in the aspects of knee clunk or crepitus, forgotten joint score, blood loss, opioid dosage and postoperative hospital stay.

Purinoceptors, renal microvascular function and hypertension.

Proper renal blood flow (RBF) and glomerular filtration rate (GFR) are critical for maintaining normal blood pressure, kidney function and water and electrolyte homeostasis. The renal microvasculature expresses a multitude of receptors mediating vasodilation and vasoconstriction, which can influence glomerular blood flow and capillary pressure. Despite this, RBF and GFR remain quite stable when arterial pressure fluctuates because of the autoregulatory mechanism. ATP and adenosine participate in autoregulatory control of RBF and GFR via activation of two different purinoceptor families (P1 and P2). Purinoceptors are widely expressed in renal microvasculature and tubules. Emerging data show altered purinoceptor signaling in hypertension-associated kidney injury, diabetic nephropathy, sepsis, ischemia-reperfusion induced acute kidney injury and polycystic kidney disease. In this brief review, we highlight recent studies and new insights on purinoceptors regulating renal microvascular function and renal hemodynamics. We also address the mechanisms underlying renal microvascular injury and impaired renal autoregulation, focusing on purinoceptor signaling and hypertension-induced renal microvascular dysfunction. Interested readers are directed to several excellent and comprehensive reviews that recently covered the topics of renal autoregulation, and nucleotides in kidney function under physiological and pathophysiological conditions (Inscho 2009, Navar et al. 2008, Carlstrom et al. 2015, Vallon et al. 2020).

[Analysis of neurobehavioral function of school-aged children with sleep disordered breathing].

Objective: To investigate the neurobehavioral function(attention, executive skills, behavior) of school-aged with varying degrees of SDB and control children with no history of SDB recruited from the community.Method: One hundred and sixty-three children aged from 7 to 12 were enrolled in the study. Children were devided into 4 groups through the data of Routine overnight polysomnography(PSG): PS(n=71) group, mild OSAHS (n=29) group, moderate/severe OSAHS(n=21) group, and controls(n=42) group. The Behavior Rating Inventory of Executive Function(BRIEF) and the Child Behavior Checklist(CBCL) were used to assess attention, executive function and behavioral function. Result: There was significant difference of AHI, OAI, RAI, SAI and SpO 2 nadir between the mild/MS groups and the control/PS groups(F=1174.3, 1178.0, 2348.3, 34.7, 377.7, P<0.05). Total sleep time(TST) of the MS OSAHS group was significantly less than that in the control group(F=178.8, P<0.05). Increased rates of behavioral executive dysfunction were found depending on the SDB spectrum(F=181.2, 274.2, 284.5, P<0.05). Children with all severities of SDB had signicantly higher rates of total, internalizing and externalizing behavioral problems compared to control group(F=361.7, 168.3, 564.0, P<0.05). Conclusion:Our study suggests that behavioral, attention, and executive function difficulties are present in children with PS as well as OSAHS. These results have implications for the treatment of milder forms of SDB, particularly PS, which is commonly viewed as benign.

The relationship between the levels and function of endothelial progenitor cells and factor V Leiden and protein C deficiency in patients with primary Budd-Chiari syndrome.

OBJECTIVE: Budd-Chiari syndrome (BCS) is a life-threatening hepatic disease characterized by hepatic venous obstruction at the level of hepatic vein, hepatic venules, or inferior vena cava. No evidence reported the relationship between the endothelial progenitor cells and the deficiency of factor V Leiden and protein C in patients with primary Budd-Chiari syndrome. PATIENTS AND METHODS: We recruited participants between June 2014 and July 2015. For primary BCS group, 28 patients were collected. 20 patients were included in the NAFLD group. Another 73 healthy participants were recruited into the control group. None of the patients and participants had received interventional therapy or had undergone surgery prior to being recruited. Levels and functions of endothelial progenitor cells (EPCs) were examined. The factor V Leiden mutation, protein C deficiency and protein S deficiency were evaluated. Finally, the relationship between the levels and function of endothelial progenitor cells and factor V Leiden and protein C deficiency in patients with primary Budd-Chiari syndrome was analyzed. RESULTS: The results showed that no significant differences were found between the BCS (and NAFLD) and control group considering age, sex, BMI, smoking (p>0.05 for variables). However, significant differences were observed in TG, TC, HDL-C, white blood cells, hemoglobin, ALT, AST, ALP, γ-GT, total bilirubin, and albumin (p<0.05 for variables). Compared with the healthy participants, significant downregulation was found in BCS and NAFLD patients regarding CD34+/CD45-, late outgrowth endothelial cells (OECs) colonies, OECs proliferation, and OECs tubulogenesis (p<0.001 for variables). Among the 28 BCS patients, factor V Leiden mutation (n=10, 35.71%, OR 12.67, 95% CI 5.24-27.93) and hereditary protein C deficiency (n=4, 14.29%, OR 7.48, 95% CI 2.02-21.43) were more prevalent than those in the control group. These results suggested that factor V Leiden mutation and protein C deficiency were major risk factors for BCS. Finally, we demonstrated that factor V Leiden and protein C deficiency may negatively regulate the OECs levels and functions in BCS patients. CONCLUSIONS: It's important to improve the OECs levels and functions, and to prevent the deficiency of factor V Leiden and protein C in the treatment of BCS.

Oxidative stress induced necroptosis activation is involved in the pathogenesis of hyperoxic acute lung injury.

Necroptosis has been found to be involved in the pathogenesis of some lung diseases, but its role in hyperoxic acute lung injury (HALI) is still unclear. This study aimed to investigate contribution of necroptosis to the pathogenesis of HALI induced by hyperbaric hyperoxia exposure in a rat model. Rats were divided into control group, HALI group, Nec-1 (necroptosis inhibitor) group and edaravone group. Rats were exposed to pure oxygen at 250 kPa for 6 h to induce HALI. At 30 min before hyperoxia exposure, rats were intraperitoneally injected with Nec-1 or edaravone, and sacrificed at 24 h after hyperoxia exposure. Lung injury was evaluated by histology, lung water to dry ratio (W/D) and bronchoalveolar lavage fluid (BALF) biochemistry; the serum and plasma oxidative stress, expression of RIP1, RIP3 and MLKL, and interaction between RIP1 and RIP3 were determined. Results showed hyperoxia exposure significantly caused damage to lung and increased necroptotic cells and the expression of RIP1, RIP3 and MLKL. Edaravone pre-treatment not only inhibited the oxidative stress in HALI, but also reduced necroptotic cells, decreased the expression of RIP1, RIP3 and MLKL and improved lung pathology. Nec-1 pretreatment inhibited necroptosis and improved lung pathology, but had little influence on oxidative stress. This study suggests hyperoxia exposure induces oxidative stress may activate necroptosis, involving in the pathology of HALI, and strategies targeting necroptosis may become promising treatments for HALI.

High MYBL2 expression and transcription regulatory activity is associated with poor overall survival in patients with hepatocellular carcinoma.

PURPOSE: In this study, we aimed to assess the association between MYBL2 expression/transcription regulatory activity (TRA) and overall survival (OS) in patients with primary hepatocellular carcinoma (HCC) and to explore the factors related to B-Myb TRA. MATERIALS AND METHODS: Bioinformatic analysis was performed based on data from the cancer genome atlas-liver hepatocellular carcinoma (TCGA-LIHC) and the human protein atlas (HPA). RESULTS: The death group in TCGA-LIHC had significantly higher MYBL2 RNA and exon expression than the censor group. The high MYBL2 RNA and exon expression groups had significantly worse OS (P<0.01). Univariate and multivariate analysis confirmed that high MYBL2 expression was an independent prognostic factor of unfavourable OS (HR=1.591, 95%CI: 1.119-2.262, P=0.01). One hundred and fourteen out of 188 primary HCC cases in TCGA-LIHC had elevated transcription of B-Myb's downstream genes. High B-Myb TRA was associated with poor OS (P=0.013). Elevated expression of MYBL2, LIN9, LIN52 and FOXM1 were related to the higher TRA of B-Myb in HCC. CONCLUSION: High MYBL2 expression/TRA are associated with inferior OS in patients with primary HCC. Increased expression of MYBL2, LIN9, LIN52 and FOXM1 are related to higher TRA of B-Myb in HCC.

Mir-138-5p acts as a tumor suppressor by targeting pyruvate dehydrogenase kinase 1 in human retinoblastoma.

OBJECTIVE: MicroRNAs have caught more attention for their role in tumor progression. Retinoblastoma (RB) is one of these ordinary malignant tumors. This study aims to identify whether mir-138-5p can regulate the development of RB, and find out its potential mechanism. MATERIALS AND METHODS: Mir-138-5p expression in RB cells was monitored by RT-qPCR. Besides, the role of mir-138-5p in RB development was explored through function experiments in vitro. The potential mechanism was further explored by RT-qPCR, luciferase assay, and Western blot assay. RESULTS: In our investigation, mir-138-5p was lower-expressed in RB cells than that in retinal pigment epithelial cells. Moreover, overexpression of mir-138-5p repressed cell viability, migration and invasion, and induced apoptosis of RB cells, while downregulated mir-138-5p increased cell viability, migration and invasion, and reduced apoptosis of RB cells. Furthermore, pyruvate dehydrogenase kinase 1 (PDK1) could be downregulated via overexpression of mir-138-5p, while PDK1 was upregulated via knockdown of mir-138-5p. CONCLUSIONS: Our results suggested that mir-138-5p could repress the development of RB via suppressing PDK1, which may offer a new vision for interpreting the mechanism of RB tumorigenesis.

Oesophagogastric invagination.

Oesophagogastric invagination is a relatively rare disease that is primarily caused by a sliding hiatal hernia. We report a successfully treated case of oesophagogastric invagination caused by achalasia. Oesophagogastric invagination should be considered in patients complaining of upper abdominal discomfort.

[Antagonism of lovastatin on oxidative stress and apoptosis in primary rat hippocampal neurons induced by ß-amyloid peptide].

Objective: To investigate the effect of lovastatin on oxidative stress and apoptosis in neurons induced by ß-amyloid peptide (Aß). Methods: Primary culture of rat hippocampal neuron was treated with Aß oligomers alone or combined with lovastatin. The levels of OH(-), H(2)O(2), O(2)·(-), malondialdehyde, superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities were measured by biochemical methods and protein expression of caspase-3 and bcl-2 was detected by Western blot. Results: As compared with the control group, treatment of 0.5 µmol/L Aß oligomers for 48 h led to significant increase of OH(-), H(2)O(2), O(2)·(-) and malondialdehyde content, inhibition of SOD and GSH-PX activities, enhanced caspase-3 expression and decreased bcl-2 expression. Interestingly, these neurotoxic modifications on the levels of OH(-), H(2)O(2), O(2)·(-) and malondialdehyde content, SOD and GSH-PX activities, and the protein expression of cleaved caspase-3 and bcl-2 were significantly attenuated when the cells were pretreated with 0.1 µmol/L lovastatin for 24 h before exposure of Aß oligomers. Conclusion: Lovastatin may play an important role in antagonizing the neurotoxicity of Aß through a mechanism likely related to the inhibition of oxidative stress.

Astaxanthin increases radiosensitivity in esophageal squamous cell carcinoma through inducing apoptosis and G2/M arrest.

Nowadays esophageal squamous cell carcinoma (ESCC) is primarily treated by a comprehensive approach combining surgical resection and neoadjuvant chemo- or radiotherapy. However, ESCC is resistant to radiation therapy, resulting in its invasion, infiltration, and metastasis. It usually has rapidly progressed and has a poor outcome clinically. The purpose of this study is to determine the potential radiosensitizing effect of astaxanthin (ATX) and explore the underlying mechanisms in ESCC cells in vitro. ESCC cell lines were exposure to irradiation, in the presence or absence of ATX treatment. Cell viability and radiosensitization were tested by CCK8 assay and clonogenic survival assay, respectively. Cell apoptosis and the changes of cell cycle distribution were observed by flow cytometry. The protein expression of Bcl2, Bax, CyclinB1, and Cdc2 was examined by western blot analysis. It was shown that ATX improved radiosensitivity of ESCC cells and induced apoptosis and G2/M arrest via inhibiting Bcl2, CyclinB1, Cdc2, and promoting Bax expression. In conclusion, ATX might function as a promising radiosensitizer in ESCC cells by leading to apoptosis and G2/M arrest.

[A preliminary study on macular retinal and choroidal thickness and blood flow change after posterior scleral reinforcement by optical coherence tomography angiography].

Objective: To investigate macular retinal and choroidal thickness and blood flow change using optical coherence tomography angiography after posterior scleral reinforcement (PSR) surgery. Methods: Prospective study. Twenty eyes of 10 patients with high myopia were enrolled in this open-label, single-treatment group and prospective study. Radial lines and Angio retina (3 mm×3 mm) module were performed for 20 eyes using Angio-vue optical coherence tomography (Avanti, Optovue) without pupil dilation, and best corrected visual acuity, spherical equivalent and axial length were compared before and 60 days after surgery. Retinal and choroidal thickness was measured in the fovea, 1 mm superior, 1 mm inferior, 1 mm nasal and 1 mm temporal to the fovea. Flow area, flow density and flow index were recorded using self-provided software in the superficial retina layer, deep retina layer, outer retina layer and choroid capillary layer, respectively. Statistical analysis was performed using SPSS 16.0. Data that followed normal distribution were compared with paired two-sample t-test, while others were compared with Wilcoxon signed rank test. Results: Of the patients participating in this preliminary study, the mean age was (35.5±4.2) years, and 50% were female. No significant difference was found between before and 60 days after PSR surgery in best corrected visual acuity (t=0.99, P=0.33), spherical equivalent (t=-1.89, P=0.07) and axial length (t=0.2, P=0.08). The retinal thickness in the fovea was thinner (Z=-2.58, P=0.01), while there was no significant difference in the 1 mm superior (t=0.44, P=0.67) , 1 mm inferior (t=0.05, P=0.96) , 1 mm nasal (Z=0.87, P=0.64) and 1 mm temporal (Z=-0.78, P=0.99) to the fovea. No significant difference was found in choroidal thickness (t=-0.12, P=0.87; t=-0.25, P=0.81. t=0.53, P=0.61; t=-0.91, P=0.38. t=1.2, P=0.25) before and after surgery. The postoperative flow density in the superficial and deep retinal layers (48.18±4.56% and 31.47±5.11%) was significantly increased (t=2.66, P=0.02; t=3.16, P=0.01) compared with pre-operation (33.82±4.33% and 14.29±3.89%). The postoperative flow index in the superficial and deep retina layers (0.044±0.005 and 0.025±0.005) was significantly increased (t=2.59, P=0.02. t=2.95, P=0.01) compared with pre-operation (0.028±0.004 and 0.010±0.003). The other flow measurements showed no significant difference. Conclusion: Retinal thickness decreased, and flow density and index increased in the superficial and deep retinal layers after PSR surgery. This suggested blood flow improvement in the macular region after PSR surgery in high myopic eyes. (Chin J Ophthalmol, 2017, 53:39-45).

The BM2 protein of influenza B virus interacts with p53 and inhibits its transcriptional and apoptotic activities.

The influenza virus integral membrane proteins BM2 (M2 of influenza B virus) and A/M2 (M2 of influenza A virus) functions as an ion channel, important for virus uncoating in endosomes of virus-infected cells and essential for viral replication. M2 ion channel activity is also required to stimulate NLRP3 inflammasome activation by perturbing ionic concentrations in the Golgi. In the present study, we have investigated further the interaction between BM2 and p53 to confirm our previous studies using yeast two-hybrid assays. The interaction between BM2 and p53 was confirmed by GST pull-down, co-immunoprecipitation assays, and confocal microscopy. Expression of BM2 results in down-regulation of p53 mRNA and protein expression in a dose-dependent manner. In addition, we demonstrated that exogenous expression of BM2 functionally blocked p53-mediated transcriptional activity and apoptosis by luciferase reporter assay and TUNEL assay, respectively. Together, the present results indicate that BM2 is able to functionally interact with p53, and provide valuable insights into the modulation of p53 functions by influenza virus.

Multifocal central nervous system hemangioblastoma: a case report and review of the literature.

An effective therapy for multifocal central nervous system hemangioblastoma (CNS HB) is needed. Here, we report a case of multifocal CNS HB. A 43-year-old man was diagnosed with CNS HB by enhanced computed tomography and magnetic resonance imaging. Six solid tumors and one cystic nodule were detected in his cerebellum. The patient underwent three surgeries followed by knife radiosurgery and had regular visits after the operation. In addition, histological observation with hematoxylin and eosin staining and immunohistochemistry for α-inhibin, Ki67, and vascular endothelial growth factor further provided evidence of cerebral HB. The symptoms of the patient were prominently improved after each operation, suggesting that multiple surgeries and radiation therapy are needed to prevent the proliferation and relapse of multifocal CNS HB. In addition, long-term, regular hospital visits were useful. Furthermore, genetic diagnosis and gene-targeted therapy might be a promising strategy against familial CNS HB in the future.

Safety and efficacy of first-line bevacizumab combination therapy in Chinese population with advanced non-squamous NSCLC: data of subgroup analyses from MO19390 (SAiL) study.

BACKGROUND: Bevacizumab is a monoclonal antibody with high antitumor activity against malignant diseases. Previous studies have demonstrated the efficacy of first-line bevacizumab combination therapy in advanced, non-squamous non-small cell lung cancer (NS-NSCLC). SAiL (MO19390), an open-label, multicenter, single-arm study, evaluated the safety and efficacy of first-line bevacizumab-based treatment in clinical practice. This report presents the results of a subgroup analysis of Chinese patients enrolled in SAiL. METHODS: Chemo-naive Chinese patients with locally advanced, metastatic or recurrent NSCLC were randomized to receive Bev 15 mg/kg every 3 weeks plus carboplatin + paclitaxel for maximum of six cycles, followed by single-agent bevacizumab until disease progression. The primary endpoint was safety. Secondary endpoints included time to progression and overall survival. RESULTS: The Chinese intent-to-treat (ITT) population consists of 198 Chinese patients, among whom 107 (54 %) were non-smokers and 90 (45.5 %) were female. The median cycle of bevacizumab administration was 10 and median duration of bevacizumab treatment was 29.5 weeks. Only eight cases of severe adverse events were observed in the study, which were deemed to be related to bevacizumab. The incidence of AEs over grade 3 in Chinese ITT patients was generally low (<9 %). No new safety signals were reported. Objective response rate in 195 evaluable Chinese patients was 68.8 %, including four complete responses (2.1 %). Time to disease progression (TTP) and overall survival were 8.8 and 18.5 months, respectively. CONCLUSIONS: The safety and efficacy of first-line bevacizumab-based treatment in Chinese population with advanced NS-NSCLC are consistent with those in previous studies as well as in Asian subgroup population from SAiL study. No new safety signals were reported.