Exosomes from adipose-derived mesenchymal stem cell improve diabetic wound healing and inhibit fibrosis via miR-128-1-5p/TGF-ß1/Smad axis.

OBJECTIVE: Difficult-to-heal wound is a prevalent and significant complication of diabetes, characterized by impaired functionality of epithelial cells such as fibroblasts. This study aims to investigate the potential mechanism of ADSC-Exos promoting diabetic wound healing by regulating fibroblast function. MATERIALS AND METHODS: ADSC-Exos were confirmed through TEM, NTA, and Western Blot techniques. The study conducted on rat skin fibroblasts (RSFs) exposed to 33 mmol/L glucose in vitro. We used cck-8, EDU, transwell, and scratch assays to verify the proliferation and migration of RSFs. Furthermore, levels of TGF-ß1 and α-SMA proteins were determined by immunofluorescence and Western Blot. RSFs were transfected with miR-128-1-5p mimics and inhibitors, followed by quantification of TGF-ß1, α-SMA, Col I and Smad2/3 protein levels using Western Blot. In vivo, the effects of ADSC-Exos on diabetic wounds were assessed using digital imaging, histological staining, as well as Western Blot analysis. RESULTS: In vitro, ADSC-Exos significantly enhanced proliferation and migration of RSFs while reducing the expression of TGF-ß1 and α-SMA. In vivo, ADSC-Exos effectively promoted diabetic wound healing and mitigated scar fibrosis. Additionally, ADSC-Exos exhibited elevated levels of miR-128-1-5p, which targets TGF-ß1, resulting in a notable reduction in TGF-ß1, α-SMA, Col I and smad2/3 phosphorylation in RSFs. CONCLUSION: In conclusion, our results demonstrated that ADSC-Exos promoted diabetic wound healing, and inhibited skin fibrosis by regulating miR-128-1-5p/TGF-ß1/Smad signaling pathway, which provides a promising innovative treatment for diabetic wound healing.

Allogeneic platelet-rich plasma inhibits ferroptosis in promoting wound repair of type 2 diabetic ulcers.

Increasing evidence has revealed the emerging role of ferroptosis in the pathophysiology of type 2 diabetes mellitus (T2DM) and its complications. Platelet-rich plasma (PRP) has been demonstrated to facilitate the healing of T2DM ulcers. However, the mechanism by which PRP repairs T2DM ulcers remains unclear. Here, we sought to investigate the interaction between PRP and ferroptosis in repairing T2DM ulcers. The results showed that the cellular activity, proliferation, and migration of fibroblasts were down-regulated, and the cellular activity and normal function of vascular endothelial cells were impaired in the high glucose environment or under RSL3 conditions (a GSH peroxidase 4 inhibitor and ferroptosis inducer). Additionally, both cells experienced over-activation of multiple forms of reactive oxygen species (ROS) and lipid peroxidation. In the T2DM rat model, we observed a decreased rate of ulcer wound healing, impaired proliferative capacity, diminished vascular regeneration, and marked inflammation and hyperfibrosis. More importantly, there was typical damage to mitochondria, increased levels of iron ions, and consistent alterations in protein expression of ferroptosis-related factors. These factors include cyclooxygenase-2 (COX2), glutathione peroxidase 4 (GPX4), transferrin receptor (TFRC), and Solute Carrier Family 7 Member 11 (SLC7A11), among others. Due to the strong association between ferroptosis and T2DM ulcers, the use of allogeneic platelet-rich plasma (Al-PRP) exhibited physiological effects similar to those of the ferroptosis inhibitor Ferrostatin-1 (Fer-1). In vivo experiments, both drugs inhibited a range of impediments to wound healing caused by T2DM and ameliorated the adverse effects associated with ferroptosis. Moreover, Al-PRP attenuated the impairment of normal cellular function, activation of ROS and lipid peroxidation induced by high glucose or RSL3. These results suggested that ferroptosis was involved in the development of T2DM ulcers, which could be treated with Al-PRP by inhibiting ferroptosis, and inhibition of ferroptosis may be a suitable treatment strategy for T2DM ulcers.

Analysis of Survival Quality of Peroneal Artery Perforator Flap in Immediate Repairment and Reconstruction of Oral and Maxillofacial Malignancies.

OBJECTIVE: This study aimed to investigate the survival quality of peroneal artery perforator flap in the reconstruction of oral and maxillofacial malignant tumors. METHODS: Thirty-two cases with a diagnosis of oral and maxillofacial malignant tumors admitted to our hospital from January 2019 to December 2019 were randomly divided into 2 groups. The observation group was reconstructed with free open artery perforator flaps, and the control group was repaired with free forearm flaps. RESULTS: The observation group had significantly lower scores in terms of postoperative pain, appearance, and anxiety, compared with the control group ( P <0.05). Both groups had high scores on taste, saliva, and shoulder function although there was no significant difference ( P >0.05). The scores of the observation group were significantly higher than those in the control group in terms of chewing, swallowing, speech, activity, mood, and entertainment ( P <0.05). There was 1 case accompanied by postoperative wound dehiscence and 2 cases with wound infection in the observation group while there were 3 cases with wound dehiscence and 2 cases with wound infection in the control group ( P >0.05). CONCLUSION: Compared with the forearm flap, the peroneal artery perforator flap can improve the survival quality of patients, especially in postoperative function with the fibula joint to repair the oral and maxillofacial defects. It has a wide application prospect as one of the ideal flaps in oral and maxillofacial postoperative repair and reconstruction.

[IL-27: a novel cytokine mediating immune related diseases].

Interleukin 27 (IL-27) is a pleiotropic cytokine that is involved in the regulation of the body's innate and adaptive immunity. Previous studies have shown that IL-27 mediates a variety of inflammatory responses in vivo. With the development of animal models and technical tools, several studies have shown that it is also closely associated with autoimmune diseases and other immune related diseases, and is considered as an important candidate for the treatment of viral disease, autoimmune diseases, tumors and obesity. Therefore, this paper reviews recent progress on the role of IL-27 in acquired immunodeficiency syndrome (AIDS), rheumatoid arthritis, tumors and obesity, with the aim of providing new ideas for the treatment of immune related diseases.

Dearomatization-Rearomatization Reaction of Metal-Polarized Aza-ortho-Quinone Methides.

Metal-polarized aza-ortho-quinone methides (aza-o-QMs) are a unique and efficient handle for azaheterocycle synthesis. Despite great achievements, the potential of these reactive intermediates has not yet been fully exploited, especially the new reaction modes. Herein, we disclosed an unprecedented dearomatization process of metal-polarized aza-o-QMs, affording transient dearomatized spiroaziridine intermediates. Based on this serendipity, we accomplished three sequential dearomatization-rearomatization reactions of benzimidazolines with aza-sulfur ylides, enabling the divergent synthesis of bis-nitrogen heterocycles with high efficiency and flexibility. Moreover, experimental and theoretical studies were performed to explain the proposed mechanisms and observed selectivity. Further cellular evaluation of the dibenzodiazepine products identified a hit compound for new antitumor drugs.

Real-world study of antiresorptive-related osteonecrosis of jaw based on the US food and drug administration adverse event reporting system database.

Objective: This study aims to explore the risk signals of osteonecrosis of the jaw induced by antiresorptive drugs and provide references for the clinical safety application. Method: According to the FDA's Adverse Event Reporting System (FAERS), from January 2004 to September 2021, we chose "Osteonecrosis of the jaw (10064658)" and "Exposed bone in jaw (10071014)" as preferred terms, "antiresorptive drugs" as the target drugs, and primary suspect drug as the drug role code in the dataset. We evaluated the association between drugs and adverse events by using reporting odds ratio (ROR) based on disproportionality analysis. We took the High-Level Terms (HLT) of MedDRA® as the classification level of indications to calculate ROR to compare the signal difference of ONJ in different indications. In addition, patients with antiresorptive-induced osteonecrosis of the jaw and the time of onset of the condition following different antiresorptive medications were collected for the study. Results: The FAERS contained 18,421 reports relating to jaw osteonecrosis from January 2004 to September 2021. A total of eight antiresorptive agents were included in the analysis. From high to low, the ROR of ONJ induced by antiresorptive agents (regardless of indication) is pamidronate (ROR = 494.8), zoledronic acid (ROR = 431.9), denosumab (ROR = 194.8), alendronate (ROR = 151.2), risedronate (ROR = 140.2), etidronic acid (ROR = 64.5), ibandronate (ROR = 40.8), and romosozumab (ROR = 6.4). HLT ROR values for "metabolic bone disorders" were the lowest for each drug, while HLT ROR values were high for "tumor-related indications," including breast and nipple neoplasms malignant, plasma cell myelomas, and prostatic neoplasms malignant. The onset time for osteonecrosis of the jaw as median (Q1, Q3), osteoporosis-related indications, and the onset time for ONJ were 730 (368, 1268), 489.5 (236.3, 909.8), 722.5 (314, 1055), 761 (368, 1720), and 153 (50, 346) for zoledronic acid, denosumab, ibandronate, risedronate, and romosozumab, respectively. Cancer-related indications: the onset time for ONJ were 680.5 (255.3, 1283), 488 (245, 851), and 696.5 (347, 1087) for zoledronic acid, denosumab, and pamidronate, respectively. Conclusion: When antiresorptive drugs are used for metastasis, they have the largest risk signal, followed by malignancy, and the smallest is osteoporosis. The onset time of ONJ may not be related to the indications. The onset time of ONJ for BPs was about 2 years, denosumab about 1.3 years, and romosozumab less than 1 year, which may be related to sequential treatment. When used according to the instructions, the risk of ONJ caused by denosumab was higher than that of zoledronic acid, regardless of the indication. Based on these findings, researchers will continue to monitor and identify risk factors.

De Novo Construction of Chiral Aminoindolines by Cu-Catalyzed Asymmetric Cyclization and Subsequent Discovery of an Unexpected Sulfonyl Migration.

Searching for efficient strategies to access structurally novel aminoindolines is of great significance for drug discovery. However, catalytic asymmetric de novo construction of aminoindoline scaffolds with functionality primed for diversification still remains elusive. Here, we report a Cu-catalyzed asymmetric cyclization of ethynyl benzoxazinones with amines, producing chiral 3-aminoindolines in good yield and with high enantioselectivity (up to 97% yield and 98:2 er). Moreover, a radical-mediated sulfonyl migration of these products was unexpectedly found, further affording new chiral 3-aminoindolines bearing alkenyl sulfonyl groups with retained enantiopurity (up to 84% yield and 98:2 er). Bioactivity evaluations indicate that these 3-aminoindolines show notable antitumor activities and chirality is proven to have a significant impact on their antitumor activity.

In situ quantitative analysis by ultrasonic extraction and nebulization combined with hydrogen flame ionization mass spectrometry: Diisopropylnaphthalene (DIPN), a marker of recycled paper in packing materials.

Ambient mass spectrometry is used for direct analysis and high-throughput screening in many fields. However, most researches are about qualitative analysis. Quantitative detection based on AMS only performs on standard compounds and the relative standard deviation is so large that the accuracy of the result is low. In this study, a hydrogen flame ion source with ultrasonic nebulizer as sampling unit was established to enable solid samples to extract, nebulize and quantitatively detect in situ, with high sensitivity. This device was used to quantificationally determine the content of diisopropylnaphthalene (DIPN) in food packaging paper to identify recycled paper. Rapid analysis was performed in situ without complex pretreatment and the whole analysis time was less than 10 min. It's environmentally friendly that only 100 mg (or less) of sample and no more than 1 mL of solvent are required for one test. The external standard method was used for quantitative determination. The limit of detection was measured to be as low as 0.01 ng mL-1 and the linear dynamic range was 0.03-0.60 µg mL-1 in positive multiple reactions monitoring mode. It has been successfully applied to detect actual samples and the content of DIPN was 0.020-0.095 mg kg-1.

[Retracted] In vitro antitumor activity of the ethyl acetate extract Potentilla chinensis in osteosarcoma cancer cells.

Following the publication of the above paper, a concerned reader drew to the Editor's attention that several figures bore striking similarities to other papers that were published at around the same time written by different authors based in different research institutions. Fig. 3 (in colour) was essentially the same as a greyscale figure (Fig. 4) in a paper published in Oncology Reports, which has now been retracted [Wan G, Tao J­G, Wang G­D, Liu S­P, Zhao H­X and Liang Q­D: 3­ß­Εrythrodiol isolated from Conyza canadensis inhibits MKN­45 human gastric cancer cell proliferation by inducing apoptosis, cell cycle arrest, DNA fragmentation, ROS generation and reduces tumor weight and volume in mouse xenograft mode. Oncol Rep 35: 2328­2338, 2016]. Furthermore, Figs. 5 and 6 in the above paper appeared to share data with Figs. 7 and 11, respectively, in a paper published in Phytomedicine [Sui C­G, Meng F­D and Jiang Y­h: Antiproliferative activity of rosamultic acid is associated with induction of apoptosis, cell cycle arrest, inhibition of cell migration and caspase activation in human gastric cancer (SGC­7901) cells. Phyomedicine 22: 796­806, 2015]. After having conducted an independent investigation in the Editorial Office, the Editor of Molecular Medicine Reports has determined that the above paper should be retracted from the Journal on account of a lack of confidence concerning the originality and the authenticity of the data. The authors were asked for an explanation to account for these concerns, but the Editorial Office never received any reply. The Editor regrets any inconvenience that has been caused to the readership of the Journal. [the original article was published in Molecular Medicine Reports 14: 3634­3640, 2016; DOI: 10.3892/mmr.2016.5679].

Cysestermerol A, a rare stilbene sestermer with significant hypoglycemic activities from Cynodon dactylon.

Cysestermerol A (1), a rare and new stilbene sestermer, was isolated from the whole herb of Cynodon dactylon. The planar and relative structures of 1 were elucidated based on HRESIMS, one- and two-dimensional NMR analyses, and its absolute configuration was further established by electronic circular dichroism calculations. Compound 1 obviously increased the glucose consumption in HepG2 cells equivalent to the positive control rosiglitazone and markedly inhibited the activity of α-glucosidase in vitro.

Effect of voluntary breathing exercises on stable coronary artery disease in heart rate variability and rate-pressure product: a study protocol for a single-blind, prospective, randomized controlled trial.

BACKGROUND: At present, China has more than 11 million patients with stable coronary heart disease and this is becoming a major public health problem. The pathological changes of coronary heart disease can lead to dysfunction of the cardiac autonomic nervous system, which increases the risk of complications such as malignant arrhythmia (ventricular flutter, ventricular fibrillation, etc.), heart rate, systolic blood pressure, and rate-pressure product (RPP), which is highly correlated with myocardial oxygen consumption and indirectly reflects myocardial blood supply and oxygen consumption. Although the guidelines recommend that such patients take drugs to reduce heart rate and myocardial oxygen consumption, the clinical control of heart rate is still not ideal. Thus, in this trial, we will use voluntary breathing exercises as the strategy of exercise rehabilitation for patients with stable coronary artery disease (SCAD), in order to increase the vagus nerve activity and/or reduce the sympathetic nervous activity, help maintain or rebuild the balance of plant nerve system, improve the time-domain index of heart rate variability, reduce the burden on the heart, and relieve patients' anxiety and other negative emotions. METHODS: This is a 6-month single-blind, randomized controlled clinical trial that will be conducted in the First Affiliated Hospital of Soochow University. A total of 140 patients who fill out the Informed Consent Form are registered and randomized 1:1 into the Voluntary Breathing Exercises (VBE)-based clinical trial monitoring group (n = 70) or the Routine follow-up group (n = 70). The VBE-based clinical trial monitoring group is given VBE training on the basis of conventional treatment and health education, while the control group received conventional health education and follow-up. The primary outcomes will be measured heart rate variability and RPP. Secondary outcomes will include changes in Self-rating Anxiety Scale, total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, weight, and body mass index. DISCUSSION: This trial will carry out scientific respiratory exercise for patients with SCAD, which belongs to the category of active secondary prevention for patients, and changes from remedial to pre-protective. VBE is easy to operate and is not limited by time and place. It is important and meaningful to carry out VBE for patients with SCAD. This study will provide considerable evidence for further large-scale trials and alternative strategies for the rehabilitation nursing of patients with SCAD. TRIAL REGISTRATION: Chinese Clinical Trials Registry, 1900024043 . Registered on 23 June 2019.

The protective effects of long non-coding RNA-ANCR on arterial calcification.

INTRODUCTION: Arterial calcification is a major factor for cardiovascular events and is characterized by vascular smooth muscle cells (VSMCs) transformed into osteoblast-like cells. Long non-coding RNAs (lncRNA) were recognized as important regulators of diverse biological processes. Previous studies have demonstrated that lncRNAs could regulate the proliferation and apoptosis of VSMCs. LncRNA-ANCR (Anti-differentiation ncRNA) is an essential mediator governing the differentiation of human osteoblast. However, it is unclear whether ANCR could regulate the osteoblastic differentiation of VSMCs. In this study, we determined the effect of ANCR on VSMCs differentiation and arterial calcification. MATERIALS AND METHODS: Both cellular and mouse model of arterial calcification were, respectively, established to investigate the role of ANCR in the mechanism of arterial calcification. ANCR overexpressing lentivirus were used to investigate the effects of ANCR on the expression of bone proteins and autophagy-related molecules. RESULTS: ANCR could inhibit ß-glycerophosphate (ß-GP)-induced VSMCs osteoblastic differentiation and mineralization due to decreased expressions of Runt-related transcription factor 2, bone morphogenetic protein-2, and formation of mineralized nodule, and attenuate high calcitriol-induced mice model of arterial calcification. Furthermore, ANCR could significantly increase LC3 and autophagy protein 5 expression in ß-GP-stimulated VSMCs, and the effect could be inhibited by 3-methyladenine, a pharmacological inhibitor of autophagy. CONCLUSION: ANCR may inhibit the osteoblastic differentiation of VSMCs and attenuate mice arterial calcification through activating autophagy.

Septic pulmonary embolism in China: clinical features and analysis of prognostic factors for mortality in 98 cases.

BACKGROUND: To investigate the clinical features of septic pulmonary embolism (SPE) cases and prognostic factors for in-hospital mortality in China. METHODS: A retrospective analysis was conducted of SPE patients hospitalized between January 2007 and June 2018 in the Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University. RESULTS: A total of 98 patients with SPE were identified. All patients had bilateral multiple peripheral nodules on chest computed tomography. The most common pathogen found in blood culture was Staphylococcus aureus (10/33, 30.3%). Transthoracic echocardiography was performed in 39 patients and 20 showed vegetations. Bronchoscopy was performed in 24 patients. Bronchoalveolar lavage fluid (BALF) was obtained from 15 patients (62.5%) and showed predominantly polymorphonuclear cell infiltration (52%, range of 48%~ 63%). Four patients received transbronchial lung biopsy, and histopathological examinations revealed suppurative pneumonia and organizing pneumonia. The in-hospital mortality rate was 19.4%. Age (odds ratio [OR] 1.100; 95% confidence interval [CI] 1.035-1.169), hypotension (OR 7.260; 95% CI 1.126-46.804) and ineffective or delay of empirical antimicrobial therapy (OR 7.341; 95% CI 1.145-47.045) were found to be independent risk factors for in-hospital mortality, whereas drainage treatment was found to be a protective factor (OR 0.33; 95% CI 0.002-0.677). CONCLUSIONS: SPE cases presented with nonspecific clinical manifestations and radiologic features. Blood cultures and bronchoscopy are important measures for early diagnosis and differential diagnosis. There is relationship between primary infection sites and the type of pathogen. Maintaining normal blood pressure and providing timely and appropriate initial antimicrobial therapy for effective control of the infection could improve prognosis.

Nonvolatile Memory Device Based on Copper Polyphthalocyanine Thin Films.

In this work, we report the fabrication of nonvolatile memory devices based on chemical vapor deposition-grown copper polyphthalocyanine (CuPPc) thin films. The high polymerization degree and crystallinity of the as-obtained films were confirmed by transmission electron microscopy, X-ray photoelectron spectroscopy, and UV-vis studies. It was found that the device with Au/CuPPc/indium tin oxide sandwich structure exhibits good nonvolatile memory performance with a large ON/OFF current ratio of 103 and long retention time of 1.2 × 103 s.

Practical heterogeneous photoredox/nickel dual catalysis for C-N and C-O coupling reactions.

Efficient C-N and C-O coupling reactions of aryl halides with amines and alcohols have been developed by using the strategy of heterogeneous visible light photoredox and nickel dual catalysis. Obviously, the joint use of inexpensive and bench-stable CdS and nickel salts, together with mild reaction conditions, makes these two transformations attractive for the synthetic community. This heterogeneous dual catalysis system also proved to be successful in the ligand-free catalytic hydroxylation of aryl bromide with water as a nucleophile. The practicality of this protocol is further emphasized by the scaled-up reaction and the reusability of heterogeneous photocatalysts.

Sasanquasaponin ΙΙΙ from Schima crenata Korth induces autophagy through Akt/mTOR/p70S6K pathway and promotes apoptosis in human melanoma A375 cells.

BACKGROUND: Melanoma is a high fatality skin cancer which lacks effective drugs. Sasanquasaponin, an important sort of constituents in theaceae, has been demonstrated to have potent anti-tumor effect in breast cancer and hepatocellular carcinoma. As a sasanquasaponin, we speculate that Sasanquasaponin III (SQS III) isolated from Schima crenata Korth may also have anti-tumor activity. PURPOSE: This study aims to investigate whether SQS III has anti-melanoma activity and examine the underlying mechanisms of SQS III against melanoma. METHODS/STUDY DESIGNS: The anti-proliferative effect of SQS III was assessed by cells viability assay. Annexin V-FITC/PI double staining assay was utilized for detection of apoptosis. Mitochondrial membrane potential and reactive oxygen species (ROS) production were detected using JC-1 and DCFH-DA assay, respectively. Autophagy was monitored using transmission electron microscopy (TEM) and GFP-LC3 transfection fluorescence analysis. Autophagosome-lysosome fusion and lysosomal degradation were determined using a GFP-LC3 & LAMP1 co-localization assay and DQ-BSA staining. Proteins related to apoptosis and autophagy were analyzed by Western blotting. RESULTS: Our results demonstrated that the SQS III exhibited potent anti-cancer activity in A375 cells by inducing both apoptosis and autophagy. In melanoma cells treated with SQS III, caspases were activated and PARP was cleaved, proving the occurrence of apoptosis. Mechanistic studies indicated that the pro-apoptosis activity of SQS III was mediated by death receptor pathway and mitochondrial dysfunction which was induced by ROS accumulation and reversed by the ROS inhibitor N-acetyl-cysteine (NAC). In addition to triggering apoptosis, SQS III may also cause autophagy in melanoma cells. Our results demonstrated that SQS III induced up-regulated expression of GFP-LC3, autophagosome-lysosomal fusion and lysosomal degradation. Additionally, the ROS accumulation was also involved in the activation of autophagy. Meanwhile, it was also found that after SQS III treatment, the expression of LC3-II was up-regulated and the AKT/mTOR signaling pathway was inhibited. The autophagy inhibitor 3-MA converted cytotoxicity and apoptosis of SQS III in A375 cells, which indicated that autophagy promoted the SQS III-induced apoptosis. CONCLUSION: SQS III showed potent anti-cancer activity by inducing apoptosis and autophagy, which provides insights into its possible use as a therapy for melanoma.

Three new lignanamides from the root of Lycium chinense with anti-inflammatory activity.

Three new lignanamides, that is, a new lignanamide (1), and a pair of enantiomers (2a and 2b) were isolated from the EtOAc-soluble fraction of an EtOH extract of the root of Lycium chinense. The structures of these new compounds, including their absolute configuration, were established on the basis of HR-ESI-MS, NMR spectroscopic data and quantum chemical ECD calculations. Compound 2a showed significant anti-inflammatory activity in LPS-induced RAW 264.7 macrophages with the IC50 value of 10.77 ± 2.14 µM, comparing to that of positive control quercetin (17.21 ± 0.50 µM).

Effects of Acute Fluorene-9-Bisphenol Exposure on Mouse Oocyte in vitro Maturation and Its Possible Mechanisms.

Fluorene-9-bisphenol (BHPF), a substitute of bisphenol A (BPA) used in the production of the so-called "BPA-free" plastics, has now been shown to be released from commercial plastic bottles into drinking water and has strong anti-estrogenic activity in mice, which suggests that BHPF is also an environmental toxin. However, whether BHPF exposure has effects on mouse oocyte development is unknown. In this study, the influence of acute exposure to BHPF (50-150 µM, 12 hr) on mouse oocyte maturation and its possible mechanisms were investigated. Of note, 50-µM BHPF had no effects on the maturation of mouse oocytes, whereas 100- and 150-µM BHPF significantly blocked germinal vesicle breakdown and led to the failure of first polar body extrusion. Particularly, 100-µM BHPF exposure severely decreased the cellular adenosine triphosphate in a time-dependent manner, which finally brought out the loss of spindles. In addition, the actin cytoskeleton was also impaired. The defective mitochondrial dynamics and decreased mitochondrial DNA implied the damage of mitochondria in BHPF-treated oocytes. Increased PINK1, Beclin1, and LC3B protein level and decreased TOMM20 and TOMM17A protein level illustrated that mitophagy was induced, which also confirmed that BHPF exposure impaired the cellular mitochondria. Moreover, BHPF induced reactive oxygen species accumulation and early apoptosis. Oocyte quality was also impaired by BHPF exposure through altering histone modifications evidenced by increased H3K9me3 and H3K27me3 levels. Collectively, our results indicated that BHPF exposure disrupted mouse oocyte maturation and reduced oocyte quality through affecting cytoskeleton architecture, mitochondrial function, oxidative stress, apoptosis, and histone modifications. Environ. Mol. Mutagen. 60:243-253, 2019. © 2018 Wiley Periodicals, Inc.

Meta-analysis of the prognostic value of long non-coding RNA PVT1 for cancer patients.

BACKGROUND: Plasmacytoma variant translocation 1 (PVT1) is reported to be dysregulated in various cancers. Therefore, this meta-analysis was performed to clarify its utility as a prognosis marker in malignant tumors. METHODS: Electronic databases, including PubMed, OVID, Cochrane Library, and Web of Science databases, were retrieved from inception to December 16, 2017. Typically, hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were calculated, so as to explore the relationship between PVT1 expression and patient survival. In addition, odds ratios (OR) were calculated to assess the association of PVT1 expression with pathological parameters. RESULTS: A total of 23 studies involving 2350 patients were included in this meta-analysis. The pooled HR suggested that high PVT1 expression levels were correlated with poor overall survival (OS, HR = 1.99, 95% CI: 1.73-2.28), disease-free survival (DFS, HR = 1.76, 95% CI: 1.45-2.14), and recurrence-free survival (RFS, HR = 1.74, 95% CI: 1.26-2.39) in cancer patients without obvious heterogeneity. Moreover, high PVT1 expression levels were also correlated with larger tumor size (OR = 1.47, 95% CI: 1.02-2.11), poor differentiation grade (OR = 1.79, 95% CI: 1.39-2.30), advanced tumor stage (pooled OR = 3.28, 95% CI: 2.46-4.38), lymph node metastasis (OR = 2.67, 95% CI: 1.66-4.29) and distant metastasis (OR = 4.00, 95% CI: 1.39-11.50) in cancer patients. CONCLUSIONS: Findings of this meta-analysis suggest that a high PVT1 expression level may serve as a novel biomarker of poor prognosis in cancers.

Ablation of beta subunit of protein kinase CK2 in mouse oocytes causes follicle atresia and premature ovarian failure.

Premature ovarian failure (POF), a major cause of female infertility, is a complex disorder, but the molecular mechanisms underlying the disorder are only poorly understood. Here we report that protein kinase CK2 contributes to maintaining follicular survival through PI3K/AKT pathway and DNA damage response pathway. Targeted deletion of CK2ß in mouse oocytes from the primordial follicle stage resulted in female infertility, which was attributed to POF incurring by massive follicle atresia. Downregulated PI3K/AKT signaling was found after CK2ß deletion, indicated by reduced level of phosphorylated AKT (S473, T308, and S129) and altered AKT targets related to cell survival. Further studies discovered that CK2ß-deficient oocytes showed enhanced γH2AX signals, indicative of accumulative unrepaired DSBs, which activated CHK2-dependant p53 and p63 signaling. The suppressed PI3K/AKT signaling and failed DNA damage response signaling probably contribute to large-scale oocyte loss and eventually POF. Our findings provide important new clues for elucidating the mechanisms underlying follicle atresia and POF.