Generation of a human iPSC line CIPi004-A from a patient with neurofibromatosis type 1 and epilepsy harboring a heterozygous mutation in NF1 gene.

The NF1 gene is related to neurofibromatosis type 1 (NF1), which is an autosomal dominant disorder associated with multisystem involvement and epilepsy susceptibility. A human induced pluripotent stem cell (iPSC) line was derived from a pediatric patient with NF1 and epilepsy, harboring a heterozygous NF1 gene mutation. The iPSC line exhibits high levels of pluripotency markers, maintains the NF1 gene mutation, and demonstrates the capacity to undergo differentiation potential in vitro into three germ layers. The iPSC line will serve as a valuable resource for investigating the underlying mechanisms and conducting drug screening related to NF1 and NF1-associated epilepsy.

RNA editing enzymes: structure, biological functions and applications.

With the advancement of sequencing technologies and bioinformatics, over than 170 different RNA modifications have been identified. However, only a few of these modifications can lead to base pair changes, which are called RNA editing. RNA editing is a ubiquitous modification in mammalian transcriptomes and is an important co/posttranscriptional modification that plays a crucial role in various cellular processes. There are two main types of RNA editing events: adenosine to inosine (A-to-I) editing, catalyzed by ADARs on double-stranded RNA or ADATs on tRNA, and cytosine to uridine (C-to-U) editing catalyzed by APOBECs. This article provides an overview of the structure, function, and applications of RNA editing enzymes. We discuss the structural characteristics of three RNA editing enzyme families and their catalytic mechanisms in RNA editing. We also explain the biological role of RNA editing, particularly in innate immunity, cancer biogenesis, and antiviral activity. Additionally, this article describes RNA editing tools for manipulating RNA to correct disease-causing mutations, as well as the potential applications of RNA editing enzymes in the field of biotechnology and therapy.

Selenomethionine Suppress the Progression of Poorly Differentiated Thyroid Cancer via LncRNA NONMMUT014201/miR-6963-5p/Srprb Pathway.

BACKGROUND: Poorly differentiated thyroid cancer (PDTC) is a special type of thyroid cancer that threatens the life of the patients. Unfortunately, there are no effective treatments for PDTC right now, so it is urgent to search for new efficacious drugs. This experiment was designed to elucidate the effects of selenomethionine (SeMet) on PDTC in vitro and vivo. METHODS: A xenograft animal model was used to assay the volume and weight of PDTC. LncRNA NOMMMUT014201 expression was detected by fluorescence in situ hybridization and Real-time quantitative PCR (qRT-PCR). In vitro experiments were carried on in WRO cells. The Cell Counting Kit-8 assay was performed to test the effect of SeMet on the proliferation of cells. And the migration and invasion of WRO cells by the wound-healing assay, Transwell migration and invasion assays. The cell apoptosis was measured by flow cytometry. In addition, genes related to proliferation, migration, invasion and apoptosis were detected through qRT-PCR and Western Blot. RESULTS: SeMet inhibited the proliferation, migration and invasion and promoted the apoptosis of WRO cells in a dose-dependent manner. Then vivo, SeMet significantly suppressed the volume and weight of PDTC. And SeMet downregulated the expressions of Ki67, PCNA, MMP2, MMP9 and BCL2, but upregulated that of BAX and Cleaved-Caspase 3. Moreover, SeMet upregulated the level of LncRNA NOMMMUT014201 both vivo and in vitro. In addition, repression of LncRNA NOMMMUT014201 removed the inhibition effect of SeMet on WRO cell growth significantly (p<0.05). Further investigation showed that LncRNA NOMMMUT014201 downregulated the expression of miR-6963-5p in PDTC cells, but miR-6963-5p inhibited the level of Srprb. In addition, sh-LncRNA NOMMMUT014201 enhanced the proliferation, migration and invasion but inhibited the apoptosis of WRO cells. However, inhibited miR-6963-5p or overexpressed Srprb relieved the effects of sh-LncRNA NOMMMUT014201on WRO cells. CONCLUSION: Collectively, SeMet inhibits the growth of PDTC in a dose-dependent manner through LncRNA NONMMUT014201/miR-6963-5p/Srprb signal pathway, thus suggesting that SeMet might be a potential drug for PDTC treatment.

Development of mitochondrial gene-editing strategies and their potential applications in mitochondrial hereditary diseases: a review.

Mitochondrial DNA (mtDNA) is a critical genome contained within the mitochondria of eukaryotic cells, with many copies present in each mitochondrion. Mutations in mtDNA often are inherited and can lead to severe health problems, including various inherited diseases and premature aging. The lack of efficient repair mechanisms and the susceptibility of mtDNA to damage exacerbate the threat to human health. Heteroplasmy, the presence of different mtDNA genotypes within a single cell, increases the complexity of these diseases and requires an effective editing method for correction. Recently, gene-editing techniques, including programmable nucleases such as restriction endonuclease, zinc finger nuclease, transcription activator-like effector nuclease, clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats-associated 9 and base editors, have provided new tools for editing mtDNA in mammalian cells. Base editors are particularly promising because of their high efficiency and precision in correcting mtDNA mutations. In this review, we discuss the application of these techniques in mitochondrial gene editing and their limitations. We also explore the potential of base editors for mtDNA modification and discuss the opportunities and challenges associated with their application in mitochondrial gene editing. In conclusion, this review highlights the advancements, limitations and opportunities in current mitochondrial gene-editing technologies and approaches. Our insights aim to stimulate the development of new editing strategies that can ultimately alleviate the adverse effects of mitochondrial hereditary diseases.

Amelioration effects of α-viniferin on hyperuricemia and hyperuricemia-induced kidney injury in mice.

BACKGROUND: α-Viniferin, the major constituent of the roots of Caragana sinica (Buc'hoz) Rehder with a trimeric resveratrol oligostilbenoid skeleton, was demonstrated to possess a strong inhibitory effect on xanthine oxidase in vitro, suggesting it to be a potential anti-hyperuricemia agent. However, the in vivo anti-hyperuricemia effect and its underlying mechanism were still unknown. PURPOSE: The current study aimed to evaluate the anti-hyperuricemia effect of α-viniferin in a mouse model and to assess its safety profile with emphasis on its protective effect on hyperuricemia-induced renal injury. METHODS: The effects were assessed in a potassium oxonate (PO)- and hypoxanthine (HX)-induced hyperuricemia mice model by analyzing the levels of serum uric acid (SUA), urine uric acid (UUA), serum creatinine (SCRE), serum urea nitrogen (SBUN), and histological changes. Western blotting and transcriptomic analysis were used to identify the genes, proteins, and signaling pathways involved. RESULTS: α-Viniferin treatment significantly reduced SUA levels and markedly mitigated hyperuricemia-induced kidney injury in the hyperuricemia mice. Besides, α-viniferin did not show any obvious toxicity in mice. Research into the mechanism of action of α-viniferin revealed that it not only inhibited uric acid formation by acting as an XOD inhibitor, but also reduced uric acid absorption by acting as a GLUT9 and URAT1 dual inhibitor as well as promoted uric acid excretion by acting as a ABCG2 and OAT1 dual activator. Then, 54 differentially expressed (log2 FPKM ≥ 1.5, p ≤ 0.01) genes (DEGs) repressed by the treatment of α-viniferin in the hyperuricemia mice were identified in the kidney. Finally, gene annotation results revealed that downregulation of S100A9 in the IL-17 pathway, of CCR5 and PIK3R5 in the chemokine signaling pathway, and of TLR2, ITGA4, and PIK3R5 in the PI3K-AKT signaling pathway were involved in the protective effect of α-viniferin on the hyperuricemia-induced renal injury. CONCLUSIONS: α-Viniferin inhibited the production of uric acid through down-regulation of XOD in hyperuricemia mice. Besides, it also down-regulated the expressions of URAT1 and GLUT9 and up-regulated the expressions of ABCG2 and OAT1 to promote the excretion of uric acid. α-Viniferin could prevent hyperuricemia mice from renal damage by regulating the IL-17, chemokine, and PI3K-AKT signaling pathways. Collectively, α-viniferin was a promising antihyperuricemia agent with desirable safety profile. This is the first report of α-viniferin as an antihyperuricemia agent.

The White Matter Functional Abnormalities in Patients with Transient Ischemic Attack: A Reinforcement Learning Approach.

Background: Transient ischemic attack (TIA) is a known risk factor for stroke. Abnormal alterations in the low-frequency range of the gray matter (GM) of the brain have been studied in patients with TIA. However, whether there are abnormal neural activities in the low-frequency range of the white matter (WM) in patients with TIA remains unknown. The current study applied two resting-state metrics to explore functional abnormalities in the low-frequency range of WM in patients with TIA. Furthermore, a reinforcement learning method was used to investigate whether altered WM function could be a diagnostic indicator of TIA. Methods: We enrolled 48 patients with TIA and 41 age- and sex-matched healthy controls (HCs). Resting-state functional magnetic resonance imaging (rs-fMRI) and clinical/physiological/biochemical data were collected from each participant. We compared the group differences between patients with TIA and HCs in the low-frequency range of WM using two resting-state metrics: amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF). The altered ALFF and fALFF values were defined as features of the reinforcement learning method involving a Q-learning algorithm. Results: Compared with HCs, patients with TIA showed decreased ALFF in the right cingulate gyrus/right superior longitudinal fasciculus/left superior corona radiata and decreased fALFF in the right cerebral peduncle/right cingulate gyrus/middle cerebellar peduncle. Based on these two rs-fMRI metrics, an optimal Q-learning model was obtained with an accuracy of 82.02%, sensitivity of 85.42%, specificity of 78.05%, precision of 82.00%, and area under the curve (AUC) of 0.87. Conclusion: The present study revealed abnormal WM functional alterations in the low-frequency range in patients with TIA. These results support the role of WM functional neural activity as a potential neuromarker in classifying patients with TIA and offer novel insights into the underlying mechanisms in patients with TIA from the perspective of WM function.

BRAF V600E protect from cell death via inhibition of the mitochondrial permeability transition in papillary and anaplastic thyroid cancers.

BRAF T1799A mutation is the most common genetic variation in thyroid cancer, resulting in the production of BRAF V600E mutant protein reported to make cells resistant to apoptosis. However, the mechanism by which BRAF V600E regulates cell death remains unknown. We constructed BRAF V600E overexpression and knockdown 8505C and BCPAP papillary and anaplastic thyroid cancer cell to investigate regulatory mechanism of BRAF V600E in cell death induced by staurosporine (STS). Induced BRAF V600E expression attenuated STS-induced papillary and anaplastic thyroid cancer death, while BRAF V600E knockdown aggravated it. TMRM and calcein-AM staining showed that opening of the mitochondrial permeability transition pore (mPTP) during STS-induced cell death could be significantly inhibited by BRAF V600E. Moreover, our study demonstrated that BRAF V600E constitutively activates mitochondrial ERK (mERK) to inhibit GSK-3-dependent CypD phosphorylation, thereby making BRAF V600E mutant tumour cells more resistant to mPTP opening. In the mitochondria of BRAF V600E mutant cells, there was an interaction between ERK1/2 and GSKa/ß, while upon BRAF V600E knockdown, interaction of GSKa/ß to ERK was decreased significantly. These results show that in thyroid cancer, BRAF V600E regulates the mitochondrial permeability transition through the pERK-pGSK-CypD pathway to resist death, providing new intervention targets for BRAF V600E mutant tumours.

A Robust and Highly Efficient Approach for Isolation of Mesenchymal Stem Cells From Wharton's Jelly for Tissue Repair.

Mesenchymal stem cells derived from umbilical cord Wharton's Jelly (WJ-MSCs) are emerging as promising therapeutics for a variety of diseases due to their ability of regeneration and immunomodulation, and their non-tumorigenic and non-immunogenic properties. Although multiple protocols have been developed for WJ-MSC isolation, insufficient cell numbers, heterogeneous cell population, and variations in procedures between different laboratories impede further clinical applications. Here, we compared six widely used WJ-MSC isolation methods regarding cell morphology, yield, purity, proliferation rate, and differentiation potential. Based on these analyses, we identified that the inefficiency of the extracellular matrix digestion results in low cell yield. Thus, we developed a new method called "Mince-Soak-Digest (MSD)" to isolate MSCs from WJ by incorporating a soaking step to facilitate the digestion of the extracellular matrix and release of the cells. Our newly developed method generates significantly higher cell yield (4- to 10-fold higher) than six widely used methods that we tested with high purity and consistency. Importantly, by transplantation of WJ-MSCs to the rat uterus, we repair the endometrial injury and restore the fertility of the rats. In conclusion, our results provide a robust and highly efficient approach for the isolation of WJ-MSCs to restore injured tissue. The higher efficiency of MSD assures the abundance of WJ-MSCs for clinical applications. Furthermore, the reliability of MSD contributes to the standardization of WJ-MSC isolation, which eliminates the discrepancies due to isolation procedures, thus facilitating the evaluation of the efficacy of WJ-MSCs across various human clinical applications.

Safflower oil body nanoparticles deliver hFGF10 to hair follicles and reduce microinflammation to accelerate hair regeneration in androgenetic alopecia.

Androgenetic alopecia (AGA) affects physical and mental health with limited therapeutic options. Novel materials and delivery methods have considerable potential to improve the current paradigm of treatment. In this study, we used a novel plant nanoparticle of safflower oil body (SOB) loaded with human fibroblast growth factor 10 (hFGF10) to target hair follicles and accelerate hair regeneration in AGA mice with few adverse effects. Our data revealed that the average particle size of SOB-hFGF10 was 226.73 ± 9.98 nm, with a spherical and uniform structure, and that SOB-hFGF10 was quicker to preferentially penetrate into hair follicles than hFGF2 alone. Using a mouse model of AGA, SOB-hFGF10 was found to significantly improve hair regeneration without any significant toxicity. Furthermore, SOB-hFGF10 inhibited dihydrotestosterone (DHT)-induced TNF-α, IL-1ß, and IL-6 overproduction in macrophages in relation to hair follicle microinflammation, thereby enhancing the proliferation of dermal papilla cells. Overall, this study provides an applicable therapeutic method through targeting hair follicles and reducing microinflammation to accelerate hair regeneration in AGA.

Overexpression of let-7b exerts beneficial effects on the functions of human placental trophoblasts by activating the ERK1/2 signaling pathway.

The present work aimed to explore let-7b's molecular mechanisms that regulate the functions of placental trophoblasts and to examine placental let-7b expression in human pre-eclampsia (PE). Human trophoblast HTR-8/SVneo cells underwent transduction with control and let-7b overexpressing lentiviruses, respectively. Cell proliferation assessment utilized cell counting kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays. Apoptosis, autophagy, inflammation, epithelial-to-mesenchymal transition (EMT), and ERK1/2 signaling-associated proteins were assessed by immunoblot. Placental tissue samples were collected from women with normal pregnancy (n = 20) and PE patients (n = 14). Let-7b overexpression in HTR-8/SVneo cells remarkably induced cell proliferation and invasion, suppressed apoptosis and autophagy, and resulted in decreased tumor necrosis factorα (TNF-α) expression and increased interleukin 6 (IL-6) expression in trophoblasts. Notably, the beneficial effects of let-7b overexpression, including cell invasion and EMT, were largely reversed by treatment with U0126, an indirect ERK1/2 signaling inhibitor, in these cells. TGF-ß receptor type-1 (TGFBR1) overexpression weakened let-7b's functions in ERK pathway activation and invasion in trophoblasts. Placental tissue specimens from PE cases demonstrated significantly lower let-7b expression compared with normal controls. Overexpression of let-7b exerts beneficial effects on the functions of human placental trophoblasts via ERK1/2 signaling, and placental let-7b is downregulated in human PE. These findings suggest let-7b is a promising biomarker for the prospective diagnosis and targeted therapy of PE.

Mitochondrial Protein Translation: Emerging Roles and Clinical Significance in Disease.

Mitochondria are one of the most important organelles in cells. Mitochondria are semi-autonomous organelles with their own genetic system, and can independently replicate, transcribe, and translate mitochondrial DNA. Translation initiation, elongation, termination, and recycling of the ribosome are four stages in the process of mitochondrial protein translation. In this process, mitochondrial protein translation factors and translation activators, mitochondrial RNA, and other regulatory factors regulate mitochondrial protein translation. Mitochondrial protein translation abnormalities are associated with a variety of diseases, including cancer, cardiovascular diseases, and nervous system diseases. Mutation or deletion of various mitochondrial protein translation factors and translation activators leads to abnormal mitochondrial protein translation. Mitochondrial tRNAs and mitochondrial ribosomal proteins are essential players during translation and mutations in genes encoding them represent a large fraction of mitochondrial diseases. Moreover, there is crosstalk between mitochondrial protein translation and cytoplasmic translation, and the imbalance between mitochondrial protein translation and cytoplasmic translation can affect some physiological and pathological processes. This review summarizes the regulation of mitochondrial protein translation factors, mitochondrial ribosomal proteins, mitochondrial tRNAs, and mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) in the mitochondrial protein translation process and its relationship with diseases. The regulation of mitochondrial protein translation and cytoplasmic translation in multiple diseases is also summarized.

Extracellular Adenosine Diphosphate Stimulates CXCL10-Mediated Mast Cell Infiltration Through P2Y1 Receptor to Aggravate Airway Inflammation in Asthmatic Mice.

Asthma is an inflammatory disease associated with variable airflow obstruction and airway inflammation. This study aimed to explore the role and mechanism of extracellular adenosine diphosphate (ADP) in the occurrence of airway inflammation in asthma. The expression of ADP in broncho-alveolar lavage fluid (BALF) of asthmatic patients was determined by enzyme linked immunosorbent assay (ELISA) and the expression of P2Y1 receptor in lung tissues was determined by reverse transcription-quantitative polymerase chain reaction. Asthmatic mouse model was induced using ovalbumin and the mice were treated with ADP to assess its effects on the airway inflammation and infiltration of mast cells (MCs). Additionally, alveolar epithelial cells were stimulated with ADP, and the levels of interleukin-13 (IL-13) and C-X-C motif chemokine ligand 10 (CXCL10) were measured by ELISA. We finally analyzed involvement of NF-κB signaling pathway in the release of CXCL10 in ADP-stimulated alveolar epithelial cells. The extracellular ADP was enriched in BALF of asthmatic patients, and P2Y1 receptor is highly expressed in lung tissues of asthmatic patients. In the OVA-induced asthma model, extracellular ADP aggravated airway inflammation and induced MC infiltration. Furthermore, ADP stimulated alveolar epithelial cells to secrete chemokine CXCL10 by activating P2Y1 receptor, whereby promoting asthma airway inflammation. Additionally, ADP activated the NF-κB signaling pathway to promote CXCL10 release. As a "danger signal" extracellular ADP could trigger and maintain airway inflammation in asthma by activating P2Y1 receptor. This study highlights the extracellular ADP as a promising anti-inflammatory target for the treatment of asthma.

Efeitos Terapêuticos da Tripla Antiagregação Plaquetária em Pacientes Femininas Idosas com Diabetes e Infarto Agudo do Miocárdio / Therapeutic Effects of Triple Antiplatelet Therapy in Elderly Female Patients with Diabetes and Acute Myocardial Infarction

Resumo Fundamento A dupla antiagregação plaquetária (DAP) é o tratamento fundamental do infarto agudo do miocárdio (IAM). Objetivo O presente estudo visou investigar a eficácia e a segurança da tripla antiagregação plaquetária (TAP) em pacientes femininas idosas com diabetes e infarto agudo do miocárdio com supradesnível do segmento ST (IAMCSST), que foram submetidas à intervenção coronária percutânea ICP. Métodos Trata-se se de um estudo randomizado e mono-cego. O grupo controle A (97 pacientes idosos do sexo masculino com diabetes e STEMI, cujos escores CRUSADE foram < 30) recebeu aspirina, ticagrelor e tirofibana. Um total de 162 pacientes femininas idosas com diabetes e IAMCSST foram divididas aleatoriamente em dois grupos de acordo com o escore CRUSADE. O grupo B (69 pacientes com escore CRUSADE > 31) recebeu aspirina e ticagrelor. O grupo C (93 pacientes com escore CRUSADE < 30) recebeu aspirina, ticagrelor e tirofibana. Valores de p < 0,05 foram considerados estatisticamente significativos. Resultados Após a PCI, o fluxo sanguíneo grau 3 Thrombolysis in Myocardial Infarction (TIMI) e a perfusão miocárdica TIMI grau 3 foram significativamente menos prevalentes no grupo B, em comparação com o grupo A (p < 0,05). Quando comparada aos grupos A e C, a incidência de complicações adversas maiores foi significativamente maior no grupo B (p < 0,05). Conclusão A TAP pode efetivamente reduzir a incidência de complicações maiores em pacientes idosas com diabetes e IAMCSST. No entanto, atenção cuidadosa deve ser dada à hemorragia em pacientes que recebem TAP. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0)

Abstract Background Dual antiplatelet therapy (DAPT) is the cornerstone treatment of acute myocardial infarction (AMI). Objective The present study aimed to investigate the efficacy and safety of triple antiplatelet therapy (TAPT) in elderly female patients with diabetes and ST segment elevation myocardial infarction (STEMI), who had undergone percutaneous coronary intervention (PCI). Methods We designed a randomized, single-blind study. Control group A (97 elderly male patients with diabetes and STEMI, whose CRUSADE scores were < 30) received aspirin, ticagrelor, and tirofiban. A total of 162 elderly female patients with diabetes and STEMI were randomly divided into two groups according to CRUSADE score. Group B (69 patients with CRUSADE score > 31) received aspirin and ticagrelor. Group C (93 patients with CRUSADE score < 30) received aspirin, ticagrelor and tirofiban. P values < 0.05 were considered statistically significant. Results Compared to the findings in group A, post-PCI Thrombolysis in Myocardial Infarction (TIMI) grade 3 blood flow and TIMI myocardial perfusion grade 3 were significantly less prevalent in group B (p < 0.05). When compared to groups A and C, the incidence of major adverse complications was significantly higher in group B (p < 0.05). Conclusion TAPT could effectively reduce the incidence of major complications in elderly female patients with diabetes and STEMI. However, close attention should be paid to hemorrhage in patients receiving TAPT. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0)

Chlorogenic Acid-Induced Gut Microbiota Improves Metabolic Endotoxemia.

Background: Coffee can regulate glucose homeostasis but the underlying mechanism is unclear. This study investigated the preventive and therapeutic effects of chlorogenic acid (CGA), a polyphenol that is found in coffee, on obesity and obesity-related metabolic endotoxemia. Method: Male 4-week-old C57BL/6 mice were fed either normal chow or a high-fat diet or 20 weeks and half the mice in each group were gavaged with CGA. Oral glucose tolerance tests (OGTTs) and insulin tolerance tests (ITTs) were performed. Markers of inflammation and intestinal barrier function were assayed. The composition of the gut microbiota was analyzed by 16S rRNA high-throughput pyrosequencing. The role of CGA-altered microbiota in metabolic endotoxemia was verified by fecal microbiota transplantation. Results: CGA protected against HFD-induced weight gain, decreased the relative weight of subcutaneous and visceral adipose, improved intestinal barrier integrity, and prevented glucose metabolic disorders and endotoxemia (P <0.05). CGA significantly changed the composition of the gut microbiota and increased the abundance of short chain fatty acid (SCFA)-producers (e.g., Dubosiella, Romboutsia, Mucispirillum, and Faecalibaculum) and Akkermansia, which can protect the intestinal barrier. In addition, mice with the CGA-altered microbiota had decreased body weight and fat content and inhibited metabolic endotoxemia. Conclusion: CGA-induced changes in the gut microbiota played an important role in the inhibition of metabolic endotoxemia in HFD-fed mice.

Detection of Early Cytokine Storm in Patients with Septic Shock After Abdominal Surgery.

Objectives: To explore the characteristics of cytokine storm in patients with septic shock after abdominal surgery, examine its relationship with clinical data, and determine intervention timings. Materials and Methods: We prospectively observed a cohort of patients with abdominal infection admitted to the surgical intensive care unit (ICU) after surgery (shock group). A control group of healthy individuals was used for comparison. Plasma samples and clinical data recorded at 0, 12, 24, 48, and 72 h after surgery were collected. Cytokines (tumor necrosis factor-α, interleukin [IL]-6, IL-8, IL-10, monocyte chemotactic protein [MCP]-1, IL-1 ß, interferon-γ, IL-12p70, MCP-1α, IL-4, IL-2, and IL-13) were detected using the Luminex® technique. Results: Concentrations of most cytokines were significantly higher in the shock group. When a cytokine storm intensity curve was considered with the vasopressor dependency index and a Sequential Organ Failure Assessment (SOFA) score, time point of maximum cytokine storm intensity was earlier than that of the maximum vasopressor dependency index and SOFA score in the shock group. Conclusions: Cytokine storm occurred in patients with septic shock shortly after the abdominal surgery and may be a main mechanism leading to septic shock. Cytokine storm interventions should ideally be initiated within 24 h after surgery and be guided by cytokine storm biomarkers.

Methylation of EZH2 by PRMT1 regulates its stability and promotes breast cancer metastasis.

Enhancer of zeste homolog 2 (EZH2), a key histone methyltransferase and EMT inducer, is overexpressed in diverse carcinomas, including breast cancer. However, the molecular mechanisms of EZH2 dysregulation in cancers are still largely unknown. Here, we discover that EZH2 is asymmetrically dimethylated at R342 (meR342-EZH2) by PRMT1. meR342-EZH2 was found to inhibit the CDK1-mediated phosphorylation of EZH2 at T345 and T487, thereby attenuating EZH2 ubiquitylation mediated by the E3 ligase TRAF6. We also demonstrate that meR342-EZH2 resulted in a decrease in EZH2 target gene expression, but an increase in breast cancer cell EMT, invasion and metastasis. Moreover, we confirm the positive correlations among PRMT1, meR342-EZH2 and EZH2 expression in the breast cancer tissues. Finally, we report that high expression levels of meR342-EZH2 predict a poor clinical outcome in breast cancer patients. Our findings may provide a novel diagnostic target and promising therapeutic target for breast cancer metastasis.

Regional difference in the susceptibility of non-alcoholic fatty liver disease in China.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is a global health problem with high geographic heterogeneity. We aimed to investigate regional-specific concomitant rate of NAFLD and quantitative relationship between liver fat content (LFC) and glucose metabolism parameters in representative clinical populations from six provinces/municipalities of China. RESEARCH DESIGN AND METHODS: A total of 2420 eligible Han Chinese were enrolled consecutively from 10 clinics of obesity, diabetes and metabolic diseases located at six provinces/municipalities of China, and divided into North (Tianjin, Shandong and Heilongjiang) and South (Shanghai, Jiangsu and Henan) groups according to their geographical latitude and proximity of NAFLD concomitant rate. LFC was assessed by a quantitative ultrasound method. Multivariate regression models and analysis of covariance were used to assess the regional difference in the risk of NAFLD. RESULTS: The concomitant rate of NAFLD was 23.3%, 44.0% and 55.3% in individuals with normal glucose tolerance (NGT), pre-diabetes and diabetes, respectively. A higher concomitant rate of NAFLD was found in the participants from the North comparing with the South group, regardless of glucose metabolism status (34.7% vs 16.2% in NGT, 61.5% vs 34.7% in pre-diabetes and 67.1% vs 48.1% in diabetes). This regional difference remained significant after adjustment for age, gender, alcohol drinking, cigarette smoking, confounding metabolic parameters and liver enzymes. For any given blood glucose, participants from the North had higher LFC than those from the South group. CONCLUSIONS: Half of Han Chinese with pre-diabetes/type 2 diabetes had NAFLD, and the individuals from the North cities were more susceptible to NAFLD.

Histomorphology of vomeronasal organ in Scincella tsinlingensis / Histomorfología del órgano vomeronasal en Scincella tsinlingensis

Due to the great change in the morphology of squamate vomeronasal organ (VNO), the histomorphology characteristics of VNO in Scincella tsinlingensis were studied by light and electronic microscopy. The results indicated that the VNO of S. tsinlingensis was located at the base of nasal cavity and consisted of a mushroom body situated anteroventrally and a sensory epithelium (SE) situated dorsocaudally. SE was composed of supporting cells, receptor cells and basal cells, and the supporting cells contained secretory granules near the surface membrane. Most of receptor cells were irregular in shape with long cytoplasmic extensions and characterized by microtubules, vesicles, and mitochondria. The basal cells with long cytoplasmic extensions were also irregular in shape and appeared a greater electron density than others. The thick nerve bundles were found on the dorsomedial area of VNO, and the surface of mushroom body was non-sensory epithelium consisting of ciliated and basal cells, without goblet cells. Epithelial cells were arranged in irregular, with many cilia and microvilli distributed on its free surface. Cells on the basal layer were irregularly circular in shape and arranged sparsely. Taken together, the results indicated that the fine structure of VNO in S. tsinlingensis was similar to other species from scincomorphs.

Debido al gran cambio en la morfología del órgano vomeronasal (OVN), se estudiaron las características histomorfológicas en la Scincella tsinlingensis por microscopías de luz y electrónica. Los resultados indicaron que el OVN de S. tsinlingensis se localizaba en la base de la cavidad nasal y consistía en un cuerpo como hongo situado anteroventralmente y un epitelio sensorial (ES) situado dorso caudamente. El ES estaba compuesto de células de soporte, células receptoras y células basales, y las células de soporte contenían gránulos secretores cerca de la membrana superficial. En gran parte de la mayoría de las células receptoras se observó una forma irregular con largas extensiones citoplasmáticas, caracterizadas por microtúbulos, vesículas y mitocondrias. Las células basales con extensiones citoplasmáticas también tenían forma irregular y algunas parecían tener una mayor densidad de electrones. Los haces gruesos nerviosos se encontraron en el área dorsomedial del OVN, la superficie del cuerpo de estaba compuesto de epitelio no sensorial y consistía de células ciliadas y basales, sin células caliciformes. Las células epiteliales estaban dispuestas de manera irregular, con muchos cilios y microvellosidades distribuidas en su superficie libre. Las células en la capa basal eran escasas y de forma circular irregular. Tomados en conjunto, los resultados indicaron que la estructura fina del OVN en S. tsinlingensis era similar a otras especies de scincomorpha.

Hepatoprotective effects of hydroxysafflor yellow A in D-galactose-treated aging mice.

Hydroxysafflor yellow A (HSYA) is an effective chemical component isolated from Chinese herb Carthamus tinctorius L. In present study, we aimed to evaluate the effects of HSYA on D-galactose- (D-gal-) induced aging in mice, and to elucidate the underlying mechanism. Male C57BL/6 mice were intraperitoneal injection of D-gal and HSYA for 8 weeks. The body weight gain, spleen and thymus coefficients were determined. Levels of super dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) in serum and liver were measured using commercial kits. Pathological changes and the SA-ß-Gal activity in liver tissues were detected by hematoxylin and eosin and SA-ß-Gal staining. The expression levels of p16, CDK4, CDK6 and phosphorylation levels of Retinoblastoma (Rb) were detected by immunohistochemistry and western blot analysis. mRNA levels of genes regulated by p16-Rb pathway were determined by quantitative real-time PCR. In vivo, HSYA improved the aging changes including body weight, organ index and antioxidant status such as activities of SOD, CAT, GSH-Px and MDA in D-gal treated aging mice. HSYA also dramatically attenuated pathologic changes of aging liver tissues induced by D-gal. Furthermore, HSYA significantly decreased the mRNA and protein level of cyclin-dependent kinase inhibitor p16, followed by increasing CDK4/6 protein expression and decreasing the phosphorylation of Retinoblastoma (pRb) which up-regulated the expression of downstream genes CCNE1, CCNA2, P107 and MCM4. Collectively, these data indicated that HSYA could ameliorate aging, especially hepatic replicative senescence resulting from D-gal, the mechanism could be associated with the suppression of p16-Rb pathway.

Lung resided monocytic myeloid-derived suppressor cells contribute to premetastatic niche formation by enhancing MMP-9 expression.

In cancer patients, the prevalence of myeloid-derived suppressor cells (MDSCs) is correlated with the degree of malignancy. In the present study, we investigated the role of circulating M-MDSCs in premetastatic niche formation using a mouse syngeneic tumor model and found that there was an increased frequency of M-MDSCs in the peripheral blood of tumor-bearing mice. M-MDSCs tracking and lung tissue histological analyses revealed that the malignant conditions promote the residence of circulating M-MDSCs and increased tumor cell arrest in the lungs. We further found that MMP-9 expression was increased in the circulating M-MDSCs and the administration of an MMP-9 inhibitor suppressed M-MDSCs transplantation-induced tumor cell arrest in the lung. Therefore, our findings suggest that the expansion of circulating M-MDSCs during tumor progression contributes to premetastatic niche formation by increasing MMP-9 expression.