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1.
Arch Virol ; 166(2): 659-664, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33404858

RESUMO

The bisegmented genome of a novel double-stranded (ds) RNA mycovirus, named "Aspergillus nidulans partitivirus 1" (AnPV1), isolated from the fungus Aspergillus nidulans strain HJ5-47, was sequenced and analyzed. AnPV1 contains two segments, AnPV1-1 and AnPV1-2. AnPV1-1 has 1837 bp with an open reading frame (ORF) that potentially encodes a putative RNA-dependent RNA polymerase (RdRp) of 572 amino acids (aa). AnPV1-2 has 1583 bp with an ORF encoding a putative capsid protein (CP) of 488 aa. Phylogenetic analyses indicated that AnPV1 and related viruses clustered in a group that could represent a new unclassified genus in the family Partitiviridae.


Assuntos
Aspergillus nidulans/virologia , Micovírus/genética , Genoma Viral/genética , Vírus de RNA/genética , Sequência de Aminoácidos , Sequência de Bases , Proteínas do Capsídeo/genética , Fases de Leitura Aberta/genética , Filogenia , RNA de Cadeia Dupla/genética , RNA Viral/genética , Análise de Sequência de DNA/métodos
2.
J Trace Elem Med Biol ; 64: 126688, 2020 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-33260044

RESUMO

BACKGROUND: To reveal the underling molecular mechanism in brain damage induced by chronic fluorosis, the neurotoxicity and its correlation were investigated by transcriptomics and proteomics. METHODS: Sprague-Dawley rats were treated with fluoride at different concentrations (0, 5, 50 and 100 ppm, prepared by NaF) for 3 months. Spatial learning and memory were evaluated by Morris water maze test; neuronal morphological change in the hippocampus was observed using Nissl staining; and the level of oxidative stress including reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) were detected by biological methods. The high-throughput transcriptome sequencing (RNA-Seq) and tandem mass tag (TMT) proteomic sequencing were performed to detect the expression of differentially expressed genes and proteins, respectively. RESULTS: The results showed that compared with control group, rats exposed to high-dose fluoride exhibited declined abilities of learning and memory, decreased SOD activity and increased ROS and MDA levels, with lighter colored Nissl bodies. A total of 28 important differentially expressed genes (DEGs) were screened out by transcriptomics. Then, functional enrichment analyses showed that upregulated proteins enriched in cellular transport, while downregulated proteins enriched in synapse-related pathways. Thirteen corresponding DEGs and DAPs (cor-DEGs-DAPs) were identified by differential expressions selected with positively correlated genes/proteins, most of which were related to neurodegenerative changes and oxidative stress response. CONCLUSION: These results provide new omics evidence that rats chronically exposed to high-dose fluoride can induce neurotoxicity in the brains through changes in the cholinergic pathway and oxidative stress.

3.
Chemosphere ; : 128776, 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33131727

RESUMO

The developmental toxicity of perfluorononanoic acid (PFNA), a ubiquitous environmental contaminant, has been associated with the activation of PPARα. This study investigated influence of prenatal exposure to PFNA in pubertal activation of reproductive endocrine axis in female mice and explored underlying molecular mechanisms. Herein, we show that when PFNA (3 mg kg-1 body weight) was orally administered during gestational days 1-18, dams showed an increase in liver weight and hepatic FGF21 synthesis via PPARα activation, and their female offspring (PFNA mice) showed an increase in liver weight and hepatic FGF21 synthesis from postnatal day (PND) 1 to PND21, which were corrected by the administration of the PPARα antagonist GW6471 from PND1-14 (pup-GW). Expression of vasopressin (VAP) in the hypothalamic suprachiasmatic nucleus (SCN) was reduced in PND14-30 PFNA mice, and could be rescued by pup-GW. Pubertal activation of kisspeptin neurons in anteroventral periventricular nucleus (AVPV) and hypothalamic GnRH neurons in PND21-30 PFNA mice was obviously suppressed, but were recovered by pup-GW or PND21-30 application of VAP. The times of vaginal opening and first estrus were delayed in PFNA mice with a decrease in ovary size and the numbers of primary, secondary and antral follicles, and corpora lutea, which were relieved by pup-GW or application of VAP. The findings indicate that prenatal exposure to PFNA through increased FGF21 production in postnatal female offspring impedes postnatal activation of SCN-VAP neurons, which suppresses pubertal onset in AVPV-kisspeptin neurons and reproductive endocrine axis, leading to delayed puberty and dysfunction of ovaries.

4.
Mol Med Rep ; 22(5): 3922-3934, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33000180

RESUMO

Centromere protein M (CENPM), a protein required for chromosome separation, is involved in in mitosis. However, little has been reported about the roles of CENPM in various types of cancer. The present study identified that the mRNA expression levels of CENPM were significantly upregulated in 14 types of human cancer and identified a positive association between CENPM mRNA expression and patient mortality using the Oncomine, Gene Expression Profiling Interactive Analysis, Human Protein Atlas and Kaplan­Meier Plotter databases. A protein interaction network constructed with CENPM­interacting genes obtained from the cBioPortal demonstrated that nine genes participating in the cell cycle served key roles in the function of CENPM. Cell cycle analysis, reverse transcription­quantitative polymerase chain reaction, a Cell Counting Kit­8­based proliferation assay and a terminal deoxynucleotidyl transferase dUTP nick end labelling assay further revealed the tumorigenic and carcinogenic roles of CENPM in vitro. In addition, it was identified that the mRNA expression levels of five of the nine identified genes were significantly associated with CENPM in MCF7 cells and that CENPM was rarely mutated among various types of human cancer. In conclusion, the data from the present study revealed that CENPM exerted its pro­tumorigenic function by regulating cell cycle­associated protein expression and suggested that CENPM could be used as a prognostic marker for breast cancer.

5.
Oncol Lett ; 20(4): 68, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32863901

RESUMO

MicroRNAs (miRs) are associated with cancer metastasis. Aberrant expression levels of members of the miR-30 family have been observed in non-small-cell lung cancer (NSCLC). However, the effects of miR-30 family members on the epithelial-to-mesenchymal transition (EMT) of NSCLC cells and the underlying molecular mechanisms have not yet been fully elucidated. The present study investigated the effects of miR-30 family members on EMT, migration and invasion of NSCLC cells and found that overexpression of these miRs inhibited EMT via decreasing the expression levels of N-cadherin, ß-catenin and SNAI1, along with weakened migration and invasion abilities. Then, XB130 was identified as a downstream target of the miR-30 family members. XB130-knockdown also inhibited EMT of NSCLC cells, whereas ectopic overexpression of XB130 partly rescued the suppressive effects of miR-30c and miR-30d on EMT. In conclusion, miR-30 family members inhibited EMT of NSCLC cells, partially via suppressing XB130 expression levels.

6.
J Cardiothorac Surg ; 15(1): 207, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738925

RESUMO

BACKGROUND: Although lobectomy with mediastinal lymph node dissection (MLND) is the first option for early-stage non-small cell lung cancer (NSCLC) patients, the time trends of MLND in stage IA NSCLC patients who undergo a lobectomy are not clear still. METHODS: We included stage IA NSCLC patients who underwent lobectomy or lobectomy with MLND between 2003 and 2013 in the SEER database. The time trend of MLND was compared among patients who underwent a lobectomy. RESULTS: For stage T1a patients, the lobectomy group and lobectomy with MLND group had no differences in postoperative overall survival (OS) (P = 0.34) or lung-cancer specific survival (LCSS) (P = 0.18) between 2003 and 2013. For stage T1b patients, the OS (P = 0.01) and LCSS (P = 0.01) were different between the lobectomy group and the lobectomy with MLND group in the period from 2003 to 2009; however, only OS (P = 0.04), not LCSS (P = 0.14), was different between the lobectomy group and the lobectomy with MLND group between 2009 and 2013. For T1c patients, the OS (P = 0.01) and LCSS (P = 0.02) were different between the two groups between 2003 and 2009 but not between 2009 and 2013 (P = 0.60; P = 0.39). From the Cox regression analysis, we found that the factors affecting OS/LCSS in T1b and T1c patients were age, sex, year of diagnosis, histology, and grade, in which year of diagnosis was the obvious factor (HR = 0.79, CI = 0.71-0.87; HR = 0.73, CI = 0.64-0.84). CONCLUSIONS: There was a time trend in prognosis differences between the lobectomy group and lobectomy with MLND group for T1b and T1c stage NSCLC patients.

7.
Aging (Albany NY) ; 12(14): 14205-14218, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32701482

RESUMO

Cognitive impairment caused by diabetes has been gradually recognized. Generally, nicotinic acetylcholine receptors (nAChRs) play an important role in the pathogenesis in dementia disorders including Alzheimer's disease (AD). However, the expression of nAChRs in the brains of type 2 diabetes mellitus (T2DM) is unexplored. This study explored the alterations of nAChRs in the postmortem brains of patients with T2DM and brains of db/db mice. Morris water maze test was used to appraise the ability of spatial learning and memory; Western blotting and RT-qPCR were performed to determine the expressions of target protein and mRNA, respectively; TUNEL was used to detect the apoptosis of neurons. We found that the protein levels of nAChR α7 and α4 subunits were significantly decreased and the apoptosis rates in neurons elevated in the hippocampus of T2DM patients and db/db mice as comparison to controls. Furthermore, the db/db mice exhibited the impaired cognition, the elevated level of pro-apoptotic protein and the reduced level of anti-apoptotic and synaptic proteins. This study shows the lowered level of nAChR α7 and α4 subunits and the elevated apoptosis in the hippocampus of T2DM patients and db/db mice, which might help explain the impaired cognition in T2DM.

8.
Int J Mol Med ; 46(3): 1051-1062, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32705147

RESUMO

MicroRNAs (miRNAs/miRs) have been reported to affect ischemia/reperfusion (I/R)­induced cerebral damage. miRNAs cause post­transcriptional gene silencing by binding to the protein­coding sequence (CDS) of mRNAs. Seipin has a potential role in regulating autophagic flux. The present study investigated the involvement of miR­187­3p in Seipin expression, autophagic flux and apoptosis in vitro, as well as the underlying mechanism, using PC12 cells exposed to oxygen­glucose deprivation/reoxygenation (OGD/R), which mimicked the process of I/R. In comparison with control PC12 cells, OGD/R caused an increase in the level of miR­187­3p and a decrease in Seipin protein levels without changes in the level of Seipin mRNA. Using bioinformatics analysis, it was identified that miR­187­3p could bind to the CDS of Seipin. miR­187­3p inhibitor attenuated the reduction in Seipin protein expression in OGD/R­treated PC12 cells. Following OGD/R, autophagic flux was reduced and apoptosis was enhanced, which were attenuated by inhibition of miR­187­3p. Compared with OGD/R­treated PC12 cells, Seipin knockdown further impaired autophagic flux and promoted neuronal apoptosis, which were insensitive to inhibition of miR­187­3p. Furthermore, treatment with miR­187­3p inhibitor could decrease the infarction volume in a rat model of middle cerebral artery occlusion/reperfusion. The present findings indicated that miR­187­3p inhibitor attenuated ischemia­induced cerebral damage by rescuing Seipin expression to improve autophagic flux.

9.
Zhongguo Fei Ai Za Zhi ; 23(6): 414-418, 2020 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-32517442

RESUMO

BACKGROUND: To investigate the diagnostic significance of percutaneous lung puncture for solid pulmonary nodules (diameter ≤15 mm). METHODS: This study retrospectively included 20 patients with solid pulmonary nodules who underwent percutaneous puncture from January 2014 to December 2018, including 11 males and 9 females. The diameter of the lesion is between 0.5 cm-1.5 cm, excluding severe organ dysfunction, and patients with coagulopathy. RESULTS: All 20 patients were successfully selected, and 19 patients were diagnosed with pathological diagnosis. Among them, 11 patients found malignant tumor cells, which were clearly malignant tumors of the lungs, 5 cases of chronic inflammation of the lungs, 2 cases of fibrous tissue hyperplasia, and 1 case of lung cartilage tissue, no tumor cells were found in 1 case. One patient with a small amount of pneumothorax after puncture and one patient with a small amount of pleural effusion on the puncturesite. CONCLUSIONS: Percutaneous lung puncture has a high effectiveness and safety for the diagnosis of solid pulmonary nodules.

10.
Zhongguo Fei Ai Za Zhi ; 23(6): 492-495, 2020 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-32517454

RESUMO

BACKGROUND: Thoracoscopic safe and effective hemostasis is an important condition for rapid rehabilitation of thoracic surgery. Placing hemostatic materials during surgery is a commonly used method in lung cancer laparoscopic surgery. Among them, resorbable oxidized cellulose is a commonly used hemostatic material. This research aims to observe the hemostatic effect of resorbable oxidized cellulose in lung cancer surgery. METHODS: A retrospective analysis of 42 patients with thoracoscopic lung cancer undergoing radical surgery in the Department of Thoracic Surgery, First Affiliated Hospital of Zhejiang University School of Medicine from July 1, 2018 to December 1, 2018, and intraoperative use of regenerative oxidized cellulose to stop bleeding The clinical and pathological data were selected and the perioperative indicators were selected as the outcome events for statistical analysis. RESULTS: The mean operative time was (120.5±57.3) min. The mean intraoperative blood loss was (26.8±21.6) mL. The average postoperative drainage volume was (513.6±359.5) mL. The average postoperative chest tube indwelling time was (2.6±1.2) d. CONCLUSIONS: The use of absorbable regenerated oxidized cellulose in the radical operation of thoracoscopic lung cancer has a good hemostasis effect, and is suitable for hemostasis of wounds after lymph node dissection.

11.
Zhongguo Fei Ai Za Zhi ; 23(6): 509-513, 2020 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-32517457

RESUMO

BACKGROUND: After general thoracic surgery, a chest tube is usually placed for closed drainage to expel gas accumulation in the thoracic cavity and fluid accumulation to promote lung re-expansion. It can also be observed whether there is active bleeding after the operation and whether there is a pulmonary leak. The conventional drainage of the chest cavity is connected with a water-sealed drainage bottle, and the patient condition is judged by observing the drainage situation and the fluctuation of the water column, which is a very classic method. However, the water-sealed bottle has the disadvantages of being easy to overturn and inconvenient to carry, which is not conducive to the early activities of patients. Under the concept of accelerated rehabilitation, our center applied a new type of anhydrous thorax negative pressure drainage device and achieved good results. The purpose of this study was to observe the effect of a new type of anhydrous thoracic negative pressure drainage device in patients after thoracic surgery. METHODS: Retrospective analysis of patients who underwent lung surgery in the First Affiliated Hospital of Zhejiang University Medical College from January 2018 to December 2019, patients were divided into two groups. One group of patients used a traditional closed-chest drainage water-sealed bottle as a control group, and the other group used a new type of anhydrous negative-pressure drainage bottle as an experimental group. Patients' gender, age, hypertension, diabetes, smoking history, surgical incisions and surgical methods, and the length of hospital stay and postoperative hospital stay were calculated. RESULTS: There were no statistical differences in age, gender, comorbidities (hypertension, diabetes, smoking history), scope of surgery, and duration of surgery between the two groups of patients, but there were statistical differences in surgical incisions between the two groups of patients (P=0.01). We found that patients using the new waterless negative pressure drainage device were shorter than patients with water negative pressure drainage device in terms of postoperative hospital stay and total hospitalization time, and the difference was statistically significant (P=0.02, P=0.04). CONCLUSIONS: The new type of anhydrous thoracic negative pressure drainage device has a good effect on the rapid recovery and advancement after thoracic surgery.

12.
BMC Cancer ; 20(1): 429, 2020 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-32416716

RESUMO

BACKGROUND: Adenosquamous carcinoma (ASC) is an uncommon histological subtype of lung cancer. The purpose of this study was to assess the cumulative incidences of lung cancer-specific mortality (LC-SM) and other cause-specific mortality (OCSM) in lung ASC patients, and construct a corresponding competing risk nomogram for LC-SM. METHODS: Data on 2705 patients with first primary lung ASC histologically diagnosed between 2004 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The cumulative incidence function (CIF) was utilized to calculate the 3-year and 5-year probabilities of LC-SM and OCSM, and a competing risk model was built. Based on the model, we developed a competing risk nomogram to predict the 3-year and 5-year cumulative probabilities of LC-SM and the corresponding concordance indexes (C-indexes) and calibration curves were derived to assess the model performance. To evaluate the clinical usefulness of the nomogram, decision curve analysis (DCA) was conducted. Furthermore, patients were categorized into three groups according to the tertile values of the nomogram-based scores, and their survival differences were assessed using CIF curves. RESULTS: The 3-year and 5-year cumulative mortalities were 49.6 and 55.8% for LC-SM and 8.2 and 11.8% for OCSM, respectively. In multivariate analysis, increasing age, male sex, no surgery, and advanced T, N and M stages were related to a significantly higher likelihood of LC-SM. The nomogram showed good calibration, and the 3-year and 5-year C-indexes for predicting the probabilities of LC-SM in the validation cohort were both 0.79, which were almost equal to those of the ten-fold cross validation. DCA demonstrated that using the nomogram gained more benefit when the threshold probabilities were set within the ranges of 0.24-0.89 and 0.25-0.91 for 3-year and 5-year LCSM, respectively. In both the training and validation cohorts, the high-risk group had the highest probabilities of LC-SM, followed by the medium-risk and low-risk groups (both P < 0.0001). CONCLUSIONS: The competing risk nomogram displayed excellent discrimination and calibration for predicting LC-SM. With the aid of this individualized predictive tool, clinicians can more expediently devise appropriate treatment protocols and follow-up schedules.

13.
Mol Med Rep ; 22(1): 201-208, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32377707

RESUMO

Alzheimer's disease (AD) is a chronic and irreversible neurodegenerative disorder. Abnormal aggregation of the neurotoxic amyloid­ß (Aß) peptide is an early event in AD. The activation of astrocytic α7 nicotinic acetylcholine receptor (α7 nAChR) can inhibit Aß aggregation; thus, the molecular mechanism between α7 nAChR activation and Aß aggregation warrants further investigation. In the present study, Aß oligomer levels were assessed in astrocytic cell lysates after treatment with PNU282987 (a potent agonist of α7 nAChRs) or co­treatment with LY294002, a p­Akt inhibitor. The levels of heat shock factor­1 (HSF­1), heat shock protein 70 (HSP­70), and αB­crystallin (Cryab) in astrocytes treated with PNU282987 at various time­points or co­treated with methyllycaconitine (MLA), a selective α7 nAChR antagonist, as well as co­incubated with LY294002 were determined by western blotting. HSP­70 and Cryab levels were determined after HSF­1 knockdown (KD) in astrocytes. PNU282987 markedly inhibited Aß aggregation and upregulated HSF­1, Cryab, and HSP­70 in primary astrocytes, while the PNU282987­mediated neuroprotective effect was reversed by pre­treatment with MLA or LY294002. Moreover, the HSF­1 KD in astrocytes effectively decreased Cryab, but not HSP­70 expression. HSF­1 is necessary for the upregulation of Cryab expression, but not for that of HSP­70. HSF­1 and HSP­70 have a neuroprotective effect. Furthermore, the neuroprotective effect of PNU282987 against Aß aggregation was mediated by the canonical PI3K/Akt signaling pathway activation.

14.
Cell Signal ; 72: 109631, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32275943

RESUMO

Paclitaxel (PTX) is one of standard chemotherapy drug for patients with metastatic castration-resistant prostate cancer (mCRPC). However, PTX resistance leads to treatment failures, for which the underlying molecular mechanisms remain exclusive. In this study, we reported that PTX-induced constant HMGB1 expression and release confers to PTX resistance in mCRPC cells via activating and sustaining c-Myc signaling. PTX upregulated HMGB1 expression and triggered its release in human mCRPC cells. Silencing HMGB1 by RNAi and blocking HMGB1 release by glycyrrhizin or HMGB1 neutralizing antibody sensitized the response of PTX-resistant mCRPC cells to PTX. Release HMGB1 activated c-Myc expression. Inhibiting c-Myc expression by RNAi or c-MyC inhibitor significantly enhance the sensitivity of PTX-resistant CRPC cells to PTX. Therefore, HMGB1/c-Myc axis is critical in the development of PTX resistance, and targeting HMGB1/c-Myc axis would counteract PTX resistance in mCRPC cells.

15.
Sheng Wu Gong Cheng Xue Bao ; 36(2): 210-225, 2020 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-32147994

RESUMO

Clostridioes difficile is a Gram-positive, spore-forming, obligate anaerobic bacterium, and the main cause of hospital-associated diarrhea. In recent years, with the presence of virulent strains (i.e., ribosome type 027), the prevalence and mortality events have increased. Thus, studies on physiological and biochemical characteristics, and pathogenic mechanisms of C. difficile have been performed. The development of efficient and stable genome-editing methods for C. difficile is urgent for the dissection of its physiological and pathogenic mechanism. For example, ClosTron technology plays a key role in study of the relationship between C. difficile toxins (Toxin A and Toxin B) and its pathogenicity. This article reviews the history, recent progress and future prospects of C. difficile genome-editing technologies.


Assuntos
Edição de Genes , Proteínas de Bactérias , Toxinas Bacterianas , Composição de Bases , Enterotoxinas , Filogenia , RNA Ribossômico 16S , Análise de Sequência de DNA
16.
Aging (Albany NY) ; 12(2): 1792-1807, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-32003755

RESUMO

The aim was to determine whether the neuroprotective effect of SIRT1 in Alzheimer's disease (AD), due to inhibition of aggregation of the ß-amyloid peptide (Aß), involves activation of α7 nAChR. In present study, four-month-old APP/PS1 mice were administered resveratrol (RSV) or suramin once daily for two months, following which their spatial learning and memory were assessed using the Morris water maze test. Deposits of Aß in vivo were detected by near-infrared imaging (NIRI) and confocal laser scanning. SH-SY5Y/APPswe cells were treated with RSV, suramin, U0126 or methyllycaconitine (MLA). Levels of proteins and mRNA were determined by Western blotting and qRT-PCR, respectively. The results show that activation of SIRT1 improved their spatial learning and memory and reduced the production and aggregation of Aß in the hippocampus and cerebral cortex; whereas inhibition of SIRT1 had the opposite effects. In addition, activation of SIRT1 increased the levels of both α7 nAChR and αAPP in the brains these animals. Finally, activation of SIRT1 elevated the levels of pERK1/2, while inhibition of ERK1/2 counteracted the increase in α7 nAChR caused by RSV. These findings indicate that neuroprotection by SIRT1 may involve increasing levels of α7 nAChR through activation of the MAPK/ERK1/2 signaling pathway.

17.
Diabetologia ; 63(2): 338-350, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31776610

RESUMO

AIMS/HYPOTHESIS: Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is an autosomal recessive disorder characterised by lipodystrophy and insulin resistance. BSCL2 is caused by loss-of-function mutations in the Seipin gene (also known as Bscl2). Deletion of this gene in mice induces insulin resistance, glucose intolerance and a loss of adipose tissue. This study evaluated the effects of genetic deletion of Seipin on islet beta cell function. METHODS: We examined seipin expression in islet cells and measured glucose profiles, insulin synthesis, glucose-stimulated insulin secretion (GSIS), islet expression of peroxisome proliferator-activated receptor γ (PPARγ), levels of Pdx-1, Nkx6.1, Glut2 (also known as Slc2a2) and proinsulin mRNA, nuclear translocation of pancreatic duodenal homeobox 1 (PDX-1), islet numbers, and beta cell mass and proliferation in male and female Seipin-knockout homozygous (Seipin-/-) and heterozygous (Seipin+/-) mice. RESULTS: Male and female Seipin-/- mice displayed glucose intolerance, insulin resistance, hyperinsulinaemia and a lack of adipose tissue. By contrast, male but not female Seipin+/- mice showed glucose intolerance without adipose tissue loss or insulin resistance. Seipin was highly expressed in islet beta cells in wild-type mice. Expression of islet PPARγ was reduced in male Seipin-/- and Seipin+/- mice but not in female Seipin-/- or Seipin+/- mice. Treatment of male Seipin+/- mice with rosiglitazone corrected the glucose intolerance. Male Seipin+/- mice displayed a decrease in islet insulin concentration and GSIS with low expression of Pdx-1, Nkx6.1, Glut2 and proinsulin, and a decline in PDX-1 nuclear translocation; these changes were rescued by rosiglitazone administration. Male Seipin-/- mice showed obvious, but rosiglitazone-sensitive, increases in islet insulin concentration, islet number and beta cell mass and proliferation, with a notable decline in GSIS. Ovariectomised female Seipin+/- mice displayed glucose intolerance and deficits in insulin synthesis and secretion, with a decline in islet PPARγ level; these deleterious effects were reversed by administration of oestradiol or rosiglitazone. CONCLUSIONS/INTERPRETATION: Heterozygous deletion of Seipin in islet beta cells impacts on insulin synthesis and secretion through reduced PPARγ expression. This leads to glucose intolerance and is relieved by oestradiol, which rescues PPARγ expression.

18.
Mol Cell Probes ; 51: 101497, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31877332

RESUMO

Ischemic stroke is a common cerebrovascular disease caused by insufficient blood supply to the brain. In recent years, studies have demonstrated that microRNAs (miRNAs) are involved in a variety of biological processes in the nervous system. However, the effects of miR-202-5p on cerebral ischemic stroke injury have not been completely elucidated. In our study, N2a cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) treatment, and middle cerebral artery occlusion (MCAO) rat models were constructed. Our results indicated that decreased miR-202-5p expression was connected to N2a cells after OGD/R-induced injury and rats after MCAO. In addition, high miR-202-5p expression increased proliferation and prevented apoptosis and autophagy of OGD/R-treated N2a cells, while also effectively decreasing the infarct volume in MCAO model rats. We validated the interplay between miR-202-5p and eukaryotic translation initiation factor 4E (eIF4E), and found that miR-202-5p downregulated eIF4E by targeted combination. Moreover, we demonstrated that miR-202-5p accelerated proliferation and suppressed autophagy of OGD/R-induced N2a cells by targeting eIF4E. Meanwhile, our other results suggest that upregulation of miR-202-5p may activate the Akt/GSK-3ß pathway in ischemic brain injury. Our findings suggest that miR-202-5p may serve as a protective agent for ischemia-reperfusion injury in stroke via eIF4E.

19.
Curr Med Sci ; 40(6): 1047-1056, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33428132

RESUMO

This study aimed to elucidate the molecular mechanisms by which berberine protects against cerebral ischemia/reperfusion (I/R) injury. The oxygen-glucose deprivation/reperfusion (OGD/R) PC12 model was established. Cell counting kit-8 (CCK-8) was used to detect the toxicity of berberine and the viability of PC12 cells. Hoechst 33258 staining and flow cytometry were used to observe the nuclear morphology, and changes of apoptosis and reactive oxygen species (ROS), respectively. Western blotting and immunofluorescence assay were employed to detect autophagy-related proteins [microtubule-associated protein 1A/1B-light chain 3 (LC3), P62/SQSTM-1, Beclin-1] and endoplasmic reticulum (ER) stress-related markers [glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), Bcl-2-associated X (Bax) and cleaved caspase-3]. The GFP-RFP-LC3 adenovirus was used to assay the change of autophagic flux. Our results showed that berberine could increase the viability of PC12 cells, decrease the concentrations of ROS after OGD/R treatment, and suppress OGD/R-induced ER stress and autophagy. Moreover, the results revealed the involvement of the mammalian target of rapamycin (mTOR) pathway in the induction of autophagy, and berberine could activate the phosphorylation of mTOR and thus mitigate autophagy. In conclusion, our study suggested that berberine may protect against OGD/R-induced apoptosis by regulating ER stress and autophagy, and it holds promises in the treatment of cerebral I/R injury.

20.
Cancer Cell Int ; 19: 316, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31798345

RESUMO

Background: Glioma is a lethal malignant brain tumor, which affects the brain functions and is life-threatening. LncRNA UCA1 was identified as a pivotal regulator for tumorigenesis of glioma. MiR-206 was discovered to promote tumorigenesis and is critical in the regulation of cell proliferation in glioma. This study will discuss the expression of UCA1 regarding miR-206 and CLOCK, and their integrative effects in the proliferation and cell cycle of glioma cells. Methods: qRT-PCR was conducted to measure the mRNA expressions of IgG and Ago2 in cells co-transfected with UCA1, and miR-216 in U251. Bioinformation was analyzed for the prediction of association between UCA1 and miR-206. Transwell migrations assays and invasion assays were utilized to observe the cell invasive ability. Western blot and immunofluorescence imaging were used to examine the protein expressions. In vivo comparisons and observations were also performed to investigate the role of UCA1 in glioma growth. Results: LncRNA UCA1 was up-regulated in glioma cell lines and tissues. It elevated cell invasion via the inducing of epithelial-mesenchymal transition. We found that UCA1 can modulate miR-206 expression and serve as an endogenous sponge of miR-206. The EMT-inducer CLOCK was validated as a messenger RNA target of miR-206. At last, we demonstrated that UCA1 exerted the biology function through regulating miR-206 and CLOCK in vivo. Conclusions: Overall, the results demonstrated that UCA1/miR-206/CLOCK axis participated in the progressing of glioma and could act as a promising therapeutic target.

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