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Background and Aim: The present study aimed to investigate whether the mitochondrial K ATP channel contributes to angiotensin II (Ang II)-induced vascular dysfunction, the development of hypertension, and atherosclerosis., Methods and Results: ApoE (-/-) mice fed a high-fat diet were chronically infused with Ang II for eight weeks and concomitantly treated with losartan (ARB), apocynin, or 5-hydroxy decanoate (5-HD), or 3-methyladenine (3-MA). Systolic blood pressure was measured, and pathological changes of aortic or liver tissue were observed. Nitric oxide (NO), superoxide dismutase 2 (SOD2) levels and vasorelaxation rate were measured, and protein and mRNA expressions were examined by western blot and RT-PCR. Ang II-induced development of hypertension was suppressed not only by ARB, and apocynin but also by 5-HD or 3-MA. Ang II infusion decreased aortic NO production and relaxation, as well as SOD2 activity in liver, which were improved by all treatments. In addition, Ang II-induced activation of autophagy was suppressed by 5-HD in aortic tissue, furthermore, Ang II increases the atherosclerotic index in plasma and exacerbates the development of atherosclerosis by increases of fat deposition in the aorta and liver. Lipid metabolism-related mRNA expressions (LXR-α, LDLR, SRBI, Acca, and FASN) were changed by Ang II. Similarly, not only ARB, and apocynin, but also 5-HD and 3-MA suppressed Ang II-induced these changes., Conclusions: Our present findings evidence that mitochondrial K ATP channel-mediated autophagy contributes to Ang II-induced vascular dysfunction, development of hypertension, and atherosclerosis., Competing Interests: Declaration of competing interest Not applicable., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Whether ultra-processed food consumption is associated with cancer prognosis remains unknown. We aimed to test whether prediagnosis ultra-processed food consumption is positively associated with all-cause and cancer-specific mortality in patients with colorectal, lung, prostate, or breast cancer., Methods: This study included 1,100 colorectal cancer patients, 1750 lung cancer patients, 4,336 prostate cancer patients, and 2,443 breast cancer patients. Ultra-processed foods were assessed using the NOVA classification before the diagnosis of the first cancer. Multivariable Cox regression was used to calculate hazard ratio (HR) and 95% confidence interval (CI) for all-cause and cancer-specific mortality., Results: High ultra-processed food consumption before cancer diagnosis was significantly associated with an increased risk of all-cause mortality in lung (HR quartile 4 vs. 1 : 1.18; 95% CI: 0.98, 1.40; P trend  = 0.021) and prostate (HR quartile 4 vs. 1 : 1.18; 95% CI: 1.00, 1.39; P trend  = 0.017) cancer patients in a nonlinear dose-response manner (all P nonlinearity  < 0.05), whereas no significant results were found for other associations of interest. Subgroup analyses additionally revealed a significantly positive association with colorectal cancer-specific mortality among colorectal cancer patients in stages I and II but not among those in stages III and IV ( P interaction  = 0.006), and with prostate cancer-specific mortality among prostate cancer patients with body mass index <25 but not among those with body mass index ≥25 ( P interaction  = 0.001)., Conclusion: Our study suggests that reducing ultra-processed food consumption before cancer diagnosis may improve the overall survival of patients with lung or prostate cancer, and the cancer-specific survival of certain subgroups of patients with colorectal or prostate cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pu, Xu, Zhu, Sun, Hu, Cai, Zhang, Gong, Xiong and Zhong.)

Aims: This study aims to describe the clinical characteristics, laboratory data and complications of hospitalized COVID-19 patients with type 2 diabetes mellitus (T2DM) since epidemic prevention and control optimization was adjusted in December 2022 in China., Methods: This retrospective multicenter study included 298 patients with confirmed type 2 diabetes mellitus with or without COVID-19. We collected data from the first wave of the pandemic in The Fifth Affiliated Hospital of Guangzhou Medical University, Loudi Central Hospital and The First People's Hospital of Xiangtan from December 1, 2022 to February 1, 2023. We extracted baseline data, clinical symptoms, acute complications, laboratory findings, treatment and outcome data of each patient from electronic medical records., Results: For among 298 hospitalized patients with type 2 diabetes, 136 (45.6%) were COVID-19 uninfected, and 162 (54.4%) were COVID-19 infected. We found that the incidence of cough, fatigue, fever, muscle soreness, sore throat, shortness of breath, hyposmia, hypogeusia and polyphagia (all p<0.01) were significantly higher in the exposure group. They showed higher levels of ketone (p=0.04), creatinine (p<0.01), blood potassium (p=0.01) and more diabetic ketoacidosis (p<0.01). Patients with COVID-19 less use of metformin (p<0.01), thiazolidinediones (p<0.01) and SGLT2 (p<0.01) compared with patients without COVID-19., Conclusion: COVID-19 patients with diabetes showed more severe respiratory and constitutional symptoms and an increased proportion of hyposmia and hypogeusia. Moreover, COVID-19 patients with diabetes have a higher incidence of acute complications, are more prone to worsening renal function, and are more cautious about the use of antidiabetic drugs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhou, Huang, Lin, Zhi, Xiao, Wang, Guo, Zhou, Long, You, Lin, Luo, Sun and Zeng.)

Background: Central pontine myelinolysis (CPM) is a rare demyelinating disorder caused by the loss of myelin in the center of the basis pontis. CPM typically occurs with rapid correction of severe chronic hyponatremia and subsequent disturbances in serum osmolality. Although hyperglycaemia is recognized as a pathogenetic factor in serum osmolality fluctuations, CPM is rarely seen in the context of diabetes., Case Presentation: A 66-year-old Chinese male presented with a history of gait imbalance, mild slurred speech and dysphagia for two weeks. MRI showed the mass lesions in the brainstem, and laboratory examinations showed high blood glucose and HbA1c, as well as increased serum osmolality. The patient was diagnosed with CPM secondary to hyperosmolar hyperglyceamia and received insulin treatment as well as supportive therapy. After six weeks of followup, the patient had fully recovered to a normal state., Conclusion: CPM is a potentially fatal neurological condition and can occur in uncontrolled diabetes mellitus. Early diagnosis and timely treatment are crucial for improving the prognosis., (© 2023. The Author(s).)

Whether ultra-processed food consumption is associated with the risk of pancreatic cancer has not been determined. We performed a prospective study to fill this gap. A population-based cohort of 98 265 American adults was identified from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Ultra-processed foods were defined by the NOVA classification. Cox regression was used to estimate hazard ratios (HRs) for pancreatic cancer incidence. Subgroup analysis was performed to identify the potential effect modifiers. During a mean follow-up of 8.86 years, 387 pancreatic cancer cases occurred. High consumption of ultra-processed foods was found to be associated with an increased risk of pancreatic cancer (fully adjusted HR quartile 4 vs 1 :1.49; 95% confidence interval [CI]: 1.07-2.07; P trend  = .021) in a linear dose-response manner (P nonlinearity  = .075). Subgroup analysis further found that the positive association of ultra-processed food consumption with the risk of pancreatic cancer was more pronounced in subjects aged <65 years (HR quartile 4 vs 1 :2.17; 95% CI: 1.14-4.15) than in those aged ≥65 years (HR quartile 4 vs 1 :1.32; 95% CI: 0.88-1.94), though the interaction test failed to achieve the statistical significance (P interaction  = .061). These findings suggest that reducing ultra-processed food consumption may be beneficial in decreasing pancreatic cancer incidence., (© 2022 UICC.)

Background: Soluble suppression of tumorigenicity 2 protein (sST2) and tissue inhibitor of matrix metalloproteinase (TIMP)-1 are involved in multiple pathogenic pathways, including cardiac remodeling, which is the main pathology of atrial fibrillation (AF). This study aims to investigate the previously unexplored relationship between the serum levels of sST2, TIMP-1, and AF., Methods: This was a prospective cross-sectional study conducted at the Capital Medical University Affiliated Beijing Anzhen Hospital between June 2019 and July 2020, with a total of 359 participants. The clinical characteristics and laboratory results of the patients were compared, and multivariable ordinal logistic regression was used to evaluate the relationship between serum sST2, TIMP-1, and AF., Results: The participants included 110 patients with sinus rhythm (SR), 113 with paroxysmal AF (the paroxysmal AF group), and 136 with persistent AF (the persistent AF group). It was found that the sST2 levels gradually increased in these three groups, from 9.1 (6.7-12.4 pg/ml) in the SR group to 14.0 (10.4-20.8 pg/ml) in the paroxysmal AF group and to 19.0 (13.1-27.8) pg/ml) in the persistent AF group ( p   <  0.001). The multivariable ordinal logistic regression model for sST2 and TIMP-1 demonstrated that sST2 had an area under the receiver operating characteristic (ROC) curve (AUC) of 0.797 (95% confidence interval (CI) 0.749-0.846, p   <  0.001) and TIMP-1 had an AUC of 0.795 (95% CI 0.750-0.841, p =0.000). The multivariable ordinal logistic regression model for sST2 and TIMP-1 showed good discrimination between SR and AF, with an AUC of 0.846, and the addition of clinical factors, such as brain natriuretic peptide (BNP), left atrial diameter, age, and gender, to the biomarker model improved the detection of SR and AF (AUC 0.901)., Conclusions: In this cohort study, sST2 and TIMP-1 were associated with AF progression, independent of clinical characteristics and biomarkers. Soluble ST2 and TIMP-1 combined with age, elevated N-terminal-pro hormone BNP(NT-BNP), and an enlarged left atrium were able to demonstrate the progression of AF reliably., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Wei-Ping Sun et al.)

Purpose: The optimal time point for surgical resection of synchronous colorectal liver metastases (SCLMs) is still controversial. This meta-analysis evaluated the safety and long-term prognoses of simultaneous and staged resection of SCLM to provide a reference for clinical selection., Methods: A systematic literature search for studies published by October 2022 was performed using PubMed, Web of Science, Embase, Scopus and Cochrane Library. The evaluated outcome parameters were total, gastrointestinal and hepatic complications, as well as perioperative mortality, intraoperative blood loss, total hospital stay, 5-year disease-free survival (DFS) and 5-year overall survival (OS)., Results: This meta-analysis included 22 nonrandomised and one randomised study comprising 4862 patients. The patients undergoing simultaneous resection of SCLM had similar total (OR = 0.88, 95% CI [0.66-1.19], P = 0.409), gastrointestinal (OR = 1.19, 95% CI [0.89-1.59], P = 0.241) and hepatic (OR = 1.04, 95% CI [0.83-1.31], P = 0.734) complications, as well as perioperative mortality (OR = 1.79, 95% CI [0.88-3.64], P = 0.108), 5-year DFS (HR = 1.26, 95% CI [0.96-1.66], P = 0.098) and 5-year OS (HR = 1.13, 95% CI [0.95-1.34], P = 0.164). Lower intraoperative blood loss (SMD = - 0.39, 95% CI [- 0.60 to - 0.18], P < 0.001) and shorter total hospital stay (WMD = - 5.43, 95% CI [- 7.29 to - 3.58], P < 0.001) were observed in the simultaneous-resection group versus the staged group., Conclusions: Simultaneous resection is safe and effective for SCLM patients. The long-term prognosis is equivalent to that of the traditional staged resection. Correct selection of resectable SCLM patients for the simultaneous resection of the primary tumour and liver metastases can be the first choice. Owing to the potential heterogeneity, more RCTs should be included to verify our conclusions., (© 2022. The Author(s).)

Objectives: The previously established 38-plex InDel system was optimized and its performance was validated according to the Scientific Working Group on DNA Analysis Method (SWGDAM) application guidelines. The ancestry inference accuracy of individuals from East Asian, European, African and mixed populations was verified., Methods: DNA standard sample 9947A was used as the template to establish the optimal amplification conditions by adjusting primer balance, Mg 2+ final concentration and optimizing PCR thermal cycle parameters and amplification volume. The allelic dropout, nonspecific amplification and whether the origin of the inferred samples matched the known information were compared to evaluate the performance of this system., Results: The optimal dosage of this system was 0.125-2 ng DNA template. The results of InDel typing were accurate, the amplification equilibrium was good, and the species specificity was good. This system showed certain tolerance to DNA samples including the inhibitor such as hemoglobin (≤80 μmol/L), indigo (≤40 mmol/L), calcium ion (≤1.0 mmol/L), and humic acid (≤90 ng/μL). The system enabled the direct amplification of DNA from saliva and blood on filter paper, and the results of ethnic inference were accurate. The system successfully detected the mixed DNA sample from two individuals. The test results of the system for common biological materials in practical cases were accurate., Conclusions: The results of the 38-plex InDel system are accurate and reliable, and the performance of the system meets the requirement of the SWGDAM guidelines. This system can accurately differentiate the ancestry origins of individuals from African, European, East Asian, and Eurasian populations and can be implemented in forensic practice.

Objective: To study the clinicopathologic characteristics and risk factors of sarcoma arising in fibrous dysplasia. Methods: A total of 18 cases were collected from January 2008 to July 2018 in Shanghai Jiaotong University Affiliated Sixth People's Hospital. The characteristics and the histologic type were retrospectively reviewed. IBM SPSS 19 was used for statistical analysis. Results: The male to female ratio of patients with fibrodysplastic sarcomatosis was 1.57∶1.00. The age of onset ranged from 24 to 87 years (mean 49 years). The long bones, especially the femur, were most frequently involved. Nine cases were osteosarcomas, three cases were high grade sarcoma and six cases were low grade sarcoma. Logistic regression analysis showed that age was an independent risk factor for sarcomatous change, compared with polyostotic or recurrent cases. Value of Wals was 13.61 ( P <0.05), and odds ratio was 12.82,95% confidence interval was 3.31-49.70. Conclusions: Fibrodysplasia sarcomatosis is clinically nonspecific and the risk of sarcomatous changes increases approximately 12-fold when age of onset of fibrous dysplasia is over 40 years.

An herbal prescription is usually composed of several herbal medicines. The complex and diverse components bring great challenges to its bioactivity study. To comprehensively analyze the bioactivity of an herbal prescription, a new strategy based on peak-by-peak cutting and knock-out chromatography was proposed. In this strategy, active compounds were screened out via peak-by-peak cutting from an herbal extract, and the influence of a compound on the overall activity of the herbal extract was evaluated by knock-out chromatography. Qiliqiangxin capsule is an herbal prescription composed of 11 herbal medicines for the treatment of chronic heart failure. A total of 71 peaks were collected through peak-by-peak cutting, and each peak was identified by a high-resolution mass spectrum. The bioassay against 1,1-diphenyl-2-picrylhydrazyl showed that two types of compounds namely salvianolic acids and caffeoylquinic acids were potent scavengers. Knock-out chromatography suggested that the removal of one single compound had no obvious influence on the overall activity of the Qiliqiangxin capsule. After all the main peaks in the Qiliqiangxin capsule were knocked out, the remaining part still exhibited a potent activity, indicating high activity stability of the Qiliqiangxin capsule. The proposed strategy is helpful for the comprehensive analysis of the bioactivity of other herbal prescriptions., (© 2022 Wiley-VCH GmbH.)

Context: Current dietary guidelines recommend eggs as a part of a healthy diet. However, whether egg consumption is associated with risk of mortality remains controversial. Moreover, the dose-response association of egg consumption with risk of mortality has not been determined., Objective: To determine the potential dose-response association of egg consumption with risk of mortality in the general population., Data Sources: The PubMed and Embase databases were searched for publications meeting eligibility criteria through November 2021., Data Extraction: Required data were extracted by 1 reviewer and then checked for accuracy by another reviewer. A random-effects dose-response meta-regression model was used to calculate the pooled risk estimates. A restricted cubic spline model was used to test nonlinearity. The certainty of evidence was assessed using the GRADE system., Data Analysis: Nineteen prospective cohort studies, involving 1 737 893 participants, were included. The pooled hazard ratios for an increase of 1 egg/d were 1.08 (95%CI, 1.01-1.15) for all-cause mortality, 1.07 (95%CI, 0.97-1.18) for cardiovascular disease-caused mortality, and 1.16 (95%CI, 1.04-1.30) for cancer-caused mortality. The certainty of evidence for these observations was rated as very low. Nonlinear dose-response associations were found for egg consumption and all-cause, cardiovascular disease-caused, and cancer-caused mortality. Moreover, the positive association between egg consumption and all-cause mortality was more pronounced in studies with adjustment for blood cholesterol-related covariates than those without (Pinteraction = 0.011)., Conclusions: Greater amount of egg consumption confers higher risks of death from all causes, cardiovascular disease, and canc er in a nonlinear dose-response pattern. These findings should be treated with caution and need to be confirmed by future studies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The outbreak of COVID-19 has caused a severe shortage of healthcare resources. Ground Glass Opacity (GGO) and consolidation of chest CT scans have been an essential basis for imaging diagnosis since 2020. The similarity of imaging features between COVID-19 and other pneumonia makes it challenging to distinguish between them and affects radiologists' diagnosis. Recently, deep learning in COVID-19 has been mainly divided into disease classification and lesion segmentation, yet little work has focused on the feature correlation between the two tasks. To address these issues, in this study, we propose MultiR-Net, a 3D deep learning model for combined COVID-19 classification and lesion segmentation, to achieve real-time and interpretable COVID-19 chest CT diagnosis. Precisely, the proposed network consists of two subnets: a multi-scale feature fusion UNet-like subnet for lesion segmentation and a classification subnet for disease diagnosis. The features between the two subnets are fused by the reverse attention mechanism and the iterable training strategy. Meanwhile, we proposed a loss function to enhance the interaction between the two subnets. Individual metrics can not wholly reflect network effectiveness. Thus we quantify the segmentation results with various evaluation metrics such as average surface distance, volume Dice, and test on the dataset. We employ a dataset containing 275 3D CT scans for classifying COVID-19, Community-acquired Pneumonia (CAP), and healthy people and segmented lesions in pneumonia patients. We split the dataset into 70% and 30% for training and testing. Extensive experiments showed that our multi-task model framework obtained an average recall of 93.323%, an average precision of 94.005% on the classification test set, and a 69.95% Volume Dice score on the segmentation test set of our dataset., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To investigate the presentation of susceptibility vessel sign (SVS) in subacute stroke patients with large vessel occlusion., Methods: We collected consecutive stroke patients who were admitted to Peking University First Hospital from December 2017 to August 2019 retrospectively. Those who had intracranial large vessel occlusion and received sensitivity weighted imaging (SWI) within 3 to 14 days after stroke onset were included in our analysis. The diagnosis of large vessel occlusion was based on magnetic resonance angiography (MRA), CT angiography (CTA) or digital subtraction angiography (DSA). The demographic information, clinical characteristics and imaging results were obtained from medical record. The occurrence rates of SVS sign were compared between stroke patients with cardioembolism (CE) and large artery atherosclerosis (LAA). In the sensitivity analysis, we performed a subgroup analysis in those patients who received SWI within 7 to 14 days after stroke onset. We also compared the occurrence rate of SVS sign between the patients with and without atrial fibrillation., Results: A total of 51 patients, 19 females and 32 males, with an average age of (63.04±11.23) years were analyzed in this study. Compared with LAA group, the patients in CE group were older and more likely to have an atrial fibrillation ( P < 0.05). There were no significant differences between the CE group and LAA group in gender, hypertension, diabetes, coronary heart disease, hyperlipidemia, smoking, or National Institute of Health stroke scale(NIHSS) score at admission. SVS sign was found in 30 patients. Of whom, 3 were in CE group and 27 in LAA group. The occurrence rate of SVS sign was higher in the LAA group than in the CE group significantly (65.9% vs. 30.0%, P =0.039). The subgroup analysis showed that, in the patients who received SWI examination within 7 to 14 days after stroke onset, the differences between the two groups were still statistically significant (0 vs. 72.7%, P =0.006). Another sensitivity analysis showed that, the rate of SVS in the patients with atrial fibrillation was significantly lower than those patients without atrial fibrillation (25% vs. 65.1%, P =0.043)., Conclusion: In subacute stroke patients, the occurrence rate of SVS sign in CE group was lower than that of LAA group. The significance of SVS sign in the differentiation of stroke subtype needs further validation.

Objective: To investigate the molecular mechanism of oxaliplatin-induced chemotherapy-induced peripheral neuropathic pain (CIPNP). Methods: A total of 16 male Sprague-Dawley rats of specific pathogen-free grade were randomly divided into two groups: oxaliplatin experimental group (2.4 mg/kg oxaliplatin dissolved in 5.0% glucose solution, n =8) and control group (equal volume 5% glucose solution, n =8). The rat model of CIPNP was established by continuous administration with oxaliplatin. In addition, mechanical allodynia, thermal hyperalgesia and cold hyperalgesia were measured and compared between the two groups. To explore the molecular mechanism of oxaliplatin-induced CIPNP, the gene expression of dorsal root ganglia (DRG) from the rat model of CIPNP was analyzed using RNA sequencing (RNA-Seq). Results: Mechanical and thermal hypersensitivity was exhibited on day 7 and a stronger hypersensitivity was observed on day 14. A total of 20 152 genes were quantified by RNA-Seq, and 379 differentially expressed genes (DEGs) were obtained with absolute fold change cut-offs ≥ 2 and P value<0.05. There were 7 genes (Npy, Car3, Cdkn1a, Nts, Prc1, Ms4a7 and Ecel1) that were involved in peripheral nerve injury-related neuropathic pain. Gene ontology (GO) functional enrichment analyses indicated that the DEGs induced by oxaliplatin were involved in oxygen transport, cell division, intermediate, centromere, oxygen transporter activity, oxygen binding. Moreover, the result of Kyoto Encyclopedia of genes and genomes (KEGG) analyses highlighted that the DEGs induced by oxaliplatin were involved in malaria, African trypanosomiasis, primary immunodeficiency, peroxisome proliferator activated receptor (PPAR) signaling pathway. Conclusion: Oxaliplatin induces CIPNP via pain-related genes and signaling pathways.

Background: P53 overexpression has been shown to involve in mitochondria-mediated dapaminergic neuron cell death in Parkinson's disease. However, the exactly molecular mechanisms responsible for the p53-dependent intrinsic cell death in neurodegenerative conditions remain unclearly. Annexin A2 is a multifunctional protein that negatively regulates p53 expression. The purpose of this study was to explore the mechanism of p53 dependent dopaminergic cell death and implication of Annexin A2 in cellular apoptosis in 1-methyl-4-phenylpyridinium (MPP+)-induced PC12 cells., Methods: The cell viability of neural PC12 cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltet-razolium bromide assay. Flow cytometry was used to evaluate the apoptosis and mitochondrial transmembrane potential of neural PC12 cells. The expression of p53 and Annexin A2 was analyzed by western blot assay., Results: The present study showed that the exposure of PC12 cells to neurotoxin MPP+ increased the expression levels of p53 and the discharge of mitochondrial transmembrane potential. Notably, Annexin A2 degradation was also observed in this cellular model of Parkinson's disease, in a time and dose-dependent manner. This expressing change of Annexin A2 was in direct proportion to the loss of cell viability of PC12 cells, and this expression pattern was in inverse proportion to p53 levels in this cellular model of Parkinson's disease., Conclusion: These results indicated that Annexin A2 degradation plays a crucial role the degeneration of dapaminergic cells of Parkinson's disease, and Annexin A2 downregulation-mediated the cell death is closely associated with mitochondrial dysfunction via p53-dependent pathway; thus provide a novel therapeutic target for Parkinson's disease treatment., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

No epidemiologic studies have been conducted to assess the association of intake of dietary vitamin K with the risk of pancreatic cancer. We used prospective data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial between 1993 and 2009 to fill this gap. A total of 101,695 subjects were identified. Dietary intakes of phylloquinone (vitamin K1), menaquinones (vitamin K2), and dihydrophylloquinone (dihydrovitamin K1) were assessed using a food frequency questionnaire. Cox regression was applied to calculate hazard ratios and 95% confidence intervals. During a mean follow-up of 8.86 years (900,744.57 person-years), 361 cases of pancreatic cancer were documented. In the fully adjusted model, dietary intakes of phylloquinone (for quartile 4 vs. quartile 1, hazard ratio (HR) = 0.57, 95% confidence interval (CI): 0.39, 0.83; P for trend = 0.002) and dihydrophylloquinone (for quartile 4 vs. quartile 1, HR = 0.59; 95% CI: 0.41, 0.85; P for trend = 0.006), but not menaquinones (for quartile 4 vs. quartile 1, HR = 0.93; 95% CI: 0.65, 1.33; P for trend = 0.816), were found to be inversely associated with the risk of pancreatic cancer in a nonlinear dose-response manner (all P values for nonlinearity < 0.05), and this was not modified by predefined stratification factors and remained in sensitivity analyses. In conclusion, dietary intakes of phylloquinone and dihydrophylloquinone, but not menaquinones, confer a lower risk of pancreatic cancer. Future studies should confirm our findings., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Few studies with mixed results have examined the association between chocolate consumption and mortality. We aimed to examine this association in a US population. A population-based cohort of 91891 participants aged 55 to 74 years was identified. Chocolate consumption was assessed via a food frequency questionnaire. Cox regression was used to estimate risk estimates. After an average follow-up of 13.5 years, 19586 all-cause deaths were documented. Compared with no regular chocolate consumption, the maximally adjusted hazard ratios of all-cause mortality were 0.89 [95% confidence interval (CI) 0.84-0.94], 0.84 (95% CI 0.79-0.90), 0.86 (95% CI 0.81-0.93), and 0.87 (95% CI 0.82-0.93) for >0-0.5 servings/week, >0.5-1 serving/week, >1-2 servings/week, and >2 servings/week, respectively ( P trend = 0.009). A somewhat stronger inverse association was observed for mortality from cardiovascular disease and Alzheimer's disease. A nonlinear dose-response pattern was found for all-cause and cardiovascular mortality (all P nonlinearity < 0.01), with the lowest risk observed at chocolate consumption of 0.7 servings/week and 0.6 servings/week, respectively. The favorable associations with all-cause and cardiovascular mortality were found to be more pronounced in never smokers than in current or former smokers (all P interaction < 0.05). In conclusion, chocolate consumption confers reduced risks of mortality from all causes, cardiovascular disease, and Alzheimer's disease in this US population.

Background: Signal transduction of Angiotensin II (Ang II) induced autophagy and its role in Ang II-induced dysfunction of HUVECs are still unclear., Methods: HUVECs are stimulated with different doses of Ang II (10-9-10-5 mol/L) for different time (6-48 hours). Autophagy-related protein markers: LC3, Beclin-1 and SQSTM1/p62 are measured by western blot., Results: Incubation with Ang II increases autophagic flux (Beclin-1, autophagosomes formation, and degradation of SQSTM1/p62, LC3-I). Increased autophagic levels are inhibited by pretreatment with Ang II type 1 receptor (AT1) blocker (Candesartan), NADPH Oxidase inhibitor (apocycin), mitochondrial K ATP channels inhibitor (5-hydroxydecanoate, 5HD). 3-Methyladenine (inhibitors of autophagy) and rapamycin (activator of autophagy) respectively inhibits or activates Ang II-induced autophagy levels. Ang II decreases phosphorylation of endothelial nitric oxide synthase (eNOS) and NO production in HUVECs. L-NAME (NOS inhibitor) totally mimics the actions of Ang II on eNOS, NO production and autophagy levels. Rapamycin further decreases NO production combined with Ang II. Silence Atg5 completely reverses Ang II-activated autophagy levels., Conclusions: Our results demonstrate that Ang II stimulation increases autophagy levels via AT1 receptor, NADPH oxidase, mitochondrial K ATP channel, eNOS, Atg5 signal pathway in HUVECs, and activation of autophagy contributes to Ang II induced dysfunction of HUVECs.

Background: Modern Western diets are rich in acidogenic foods. Human and in vitro studies suggest a potential link between dietary acid load and cancer risk. However, no epidemiologic studies have investigated the association of dietary acid load with the risk of pancreatic cancer. Therefore, we conducted a prospective cohort study to fill this gap., Methods: A population-based cohort of 95,708 American adults was identified. Potential renal acid load (PRAL) and net endogenous acid production (NEAP) were used to assess dietary acid load of each subject, with greater values indicating greater dietary acid load. Cox regression was used to estimate risk estimates for pancreatic cancer incidence. Predefined subgroup analysis was used to identify the potential effect modifiers., Results: A total of 337 pancreatic cancer cases were observed during 848,534.0 person-years of follow-up. PRAL score was found to be positively associated with the risk of pancreatic cancer [fully adjusted HR quartile 4 vs. 1 : 1.73; 95% confidence interval (95% CI), 1.21-2.48; P trend = 0.001] in a nonlinear dose-response pattern ( P nonlinearity = 0.012). Subgroup analysis found that the positive association of PRAL score with the risk of pancreatic cancer was more pronounced in subjects aged <65 years than in those ≥65 years ( P interaction = 0.018). Similar results were obtained for NEAP score., Conclusions: Higher dietary acid load is associated with a higher risk of pancreatic cancer. Future studies should validate our findings in other populations and settings., Impacts: This is the first epidemiologic study suggesting that reducing dietary acid load may be useful in primary prevention of pancreatic cancer., (©2021 American Association for Cancer Research.)

Background and Aims: Aberrant transcriptional programs are highly regulated processes that play important roles in the development and progression of hepatocellular carcinoma (HCC). Emerging evidence suggests that super-enhancers (SEs) often drive critical oncogene expression. However, SE-associated genes in HCC pathogenesis are still poorly understood. Methods: We performed integrative ChIP-seq and Hi-C analyses of HCC cells and identified ajuba LIM protein (AJUBA) as a SE-associated gene. We evaluated AJUBA expression in HCC using immunohistochemistry, immunoblotting, and qRT-PCR. ChIP and luciferase reporter assays were performed to demonstrate that transcription factor 4 (TCF4) bound to AJUBA-associated SEs. We then assessed the role of AJUBA in HCC using both in vitro and in vivo assays. Epithelial-mesenchymal transition (EMT) was examined using immunofluorescence and immunoblotting assays. Furthermore, we used immunoprecipitation and BiFC assays to explore the underlying mechanisms. Results: We identified AJUBA as a SE-associated oncogene in HCC regulated by TCF4. High AJUBA expression was related to an aggressive phenotype and unfavorable outcome in HCC patients. AJUBA knockdown significantly reduced cell migration and invasion capacities both in vitro and in vivo . Furthermore, AJUBA overexpression in HCC recruited tumor necrosis factor associated factor 6 (TRAF6), enhancing the phosphorylation of Akt and increasing Akt activity toward GSK-3β, thus promoting EMT. Conclusions: Our results provide functional and mechanistic links between the SE-associated gene AJUBA and tumor EMT in aggressive HCC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background and Aims: The fecal immunochemical test (FIT) and colonoscopy are the most commonly used strategies for colorectal cancer (CRC) screening worldwide. We aimed to compare their efficacy and cost-effectiveness in CRC screening in an average-risk population., Methods: PubMed, Embase, and National Health Services Economic Evaluation Database were searched. Risk ratio (RR) was used to evaluate the differences in detection rates of colorectal neoplasia between FIT and colonoscopy groups. A random-effects model was used to pool RRs. Incremental cost-effectiveness ratios (ICERs) were calculated to evaluate the cost-effectiveness of FIT versus colonoscopy., Results: Six randomized controlled trials and 17 cost-effectiveness studies were included. The participation rate in the FIT group was higher than that in the colonoscopy group (41.6% vs 21.9%). In the intention-to-treat analysis, FIT had a detection rate of CRC comparable with colonoscopy (RR, .73; 95% confidence interval, .37-1.42) and lower detection rates of any adenoma and advanced adenoma than 1-time colonoscopy. Most included cost-effectiveness studies showed that annual (13/15) or biennial (5/6) FIT was cost-saving (ICER < $0) or very cost-effective ($0 < ICER ≤ $25000/quality-adjusted life-year) compared with colonoscopy every 10 years., Conclusions: FIT may be similar to 1-time colonoscopy in the detection rate of CRC, although it has lower detection rates of any adenoma and advanced adenoma than 1-time colonoscopy. Furthermore, annual or biennial FIT appears to be very cost-effective or cost-saving compared with colonoscopy every 10 years. These findings indicate, at least partly, that FIT is noninferior to colonoscopy in CRC screening in an average-risk population. Our findings should be treated with caution and need to be further confirmed., (Copyright © 2020 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Inflammatory cells in atherosclerotic plaque exclusively originate from hematopoietic stem/progenitor cells (HSPCs). In this study, we investigated whether circulating HSPCs frequency related to coronary stenosis in patients with coronary heart disease (CHD). Coronary angiography was performed in 468 participants who were recruited at Cardiology Centre in LuHe Hospital from March 2016 to May 2017. Among these subjects, 344 underwent echocardiography. Mononuclear cells isolated from peripheral blood were stained with an antibody cocktail containing anti-human CD34, anti-human lineage, anti-human CD38, and anti-human CD45RA. Lineage - CD38 - CD45RA dim CD34 + HSPCs were quantified by flow cytometry. CHD was defined as coronary stenosis ≥50% and the extent of CHD was further categorised by coronary stenosis ≥70%. A p < 0.0031 was regarded statistically significant by the Bonferroni correction. Circulating HSPCs frequency was 1.8-fold higher in CHD patients than non-CHD participants (p = 0.047). Multivariate-adjusted logistic analysis demonstrated that HSPCs was the only marker that was associated with the odds ratio of having mild vs. severe coronary stenosis (2.08 (95% CI, 1.35-3.21), p = 0.0009). Left ventricular ejection fraction was inversely correlated with HSPCs frequency and CRP in CHD patients (p < 0.05 for both). In conclusion, HSPCs frequency in circulation is intimately related to coronary stenoses in CHD patients.

Diabetic peripheral neuropathy is the most common complication of diabetes mellitus and leads to sensory symptoms, including diabetic neuropathic pain (DNP). DNP is a major public health problem because it has a considerable impact on life quality of diabetes mellitus patients. Therefore, development of novel effective analgesics for DNP relief and treatment is warranted. Transient receptor potential vanilloid 1 (TRPV1) has a crucial role in nociceptive transmission under pathological forms of pain. Baicalin is a flavonoid compound extracted from a medicinal herb, Huang Qin, it possesses antioxidant properties and has an analgesic effect on nitroglycerin-induced migraine in rats and neuropathic pain in spinal nerve ligation rats. However, the effects of baicalin on DNP are unclear. Therefore, the aim of this study is to examine the effects of baicalin on DNP. Our data show that a single dose of baicalin (40 µg/kg) had a transient analgesic effect on streptozotocin (STZ)-induced DNP rats. Moreover, cumulative injection of baicalin prevented the development of STZ-induced DNP in rats in a dose-dependent manner. In addition, baicalin dose-dependently suppressed the expression of TRPV1 in dorsal root ganglia of STZ-induced DNP rats. Therefore, the analgesic role of baicalin in DNP probably occurred through TRPV1. Baicalin may play an important analgesic role in DNP and might serve as a potential compound in clinical treatment and prevention of DNP.

Objective: To evaluate the effect of oltipraz (OPZ) on isoproterenol-induced heart failure (HF) and heart function. We also explore the underlying molecular mechanism of OPZ., Materials and Methods: The rats were randomly divided into four groups, including normal control group, isoproterenol (ISO) group, ISO +100 mg/kg OPZ group, and OPZ group. Hemodynamic parameters, such as left-ventricular systolic pressure, were statistically analyzed. Besides, plasma levels of brain natriuretic peptide (BNP), pro-inflammatory cytokines and antioxidant markers were assessed by using enzyme-linked immunosorbent assay (ELISA). Moreover, histopathological examination was applied to assess the degree of cardiac interstitial fibrosis., Results: OPZ could statistically improve the hemodynamic parameters of the heart function, and could also obviously attenuate cardiac interstitial fibrosis in ISO-induced HF rats when compared with the ISO group. Besides, plasma level of BNP in ISO +100 mg/kg OPZ group dramatically decreased in comparison with that of ISO group. Moreover, compared with ISO group, OPZ treatment significantly reduced the levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Moreover, OPZ treatment remarkably increased the levels of antioxidant markers such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) in ISO-induced HF rats., Conclusions: OPZ administration may provide experimental evidence for the possible effect of OPZ on isoproterenol-induced heart failure in rats. Moreover, OPZ administration may have potential utility for the treatment of heart failure.

Background: Salt-sensitive hypertension (SSH) is an intermediate inherited phenotype of essential hypertension as well as being an independent risk factor for cardiovascular disease. However, effective medications for the treatment of SSH have not been clarified. This study was to compare the efficacious of different classes of antihypertensive agents combined with salt intake on the reduction of blood pressure (BP) in patients with SSH., Methods: We used sources as PubMed, EMBASE, Cochrane Library, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, International Clinical Trials Registry Platform (ICTRP), CNKI, and WANFANG database from inception to November 2016. Studies that compared the efficacy of 2 or more antihypertensive agents or placebos in adult salt-sensitive hypertensive patients were included. The outcomes included variations in mean arterial blood pressure, systolic and diastolic blood pressure., Results: Twenty-five studies were involved in this meta-analysis. A calcium channel blocker (CCB) with hydrochlorothiazide and moderate salt intake was significantly the most efficacious in comparison with placebo (standardized mean differences (SMD), 95% credibility intervals (CI): 26.66, 12.60 to 40.16), angiotensin receptor blockers (ARBs) (SMD, 95% CI: 22.94, 5.26 to 40.51), and the other interventions for patients with SSH and no concomitant diseases. For SSH patients who were obese, CCB with metformin and moderate salt intake would decrease blood pressure with 17.90 mm Hg., Conclusions: For SSH patients with no concomitant diseases, CCB combined with hydrochlorothiazide and moderate salt intake was optimal in reducing BP, while CCB combined with metformin and moderate salt intake was the most efficacious at reducing BP in SSH patients with coexisting obesity.

Objective: Increased expression of programmed death-ligand 1 (PD-L1) on tumor cells can be found in various malignancies; however, very limited information is known about its role in anal squamous cell carcinoma (ASCC). This study explored PD-L1 expression in ASCC patients and its association with patients' clinicopathological features, CD8+ T cell infiltration, and prognosis., Methods: Formalin-fixed paraffin-embedded tumor samples from 26 patients with ASCC were retrieved. The levels of PD-L1 expression on the membrane of both tumor cells and tumor-infiltrating mononuclear cells (TIMCs) were evaluated by immunohistochemistry. CD8+ T cell densities, both within tumors and at the tumor-stromal interface, were also analyzed. Baseline clinicopathological characteristics, human papilloma virus (HPV) status, and outcome data correlated with PD-L1-positive staining., Results: PD-L1 expression on tumor cells and TIMCs was observed in 46% and 50% of patients, respectively. Nineteen patients (73%) were HPV positive, with 7 showing PD-L1-positive staining on tumor cells and 9 showing PD-L1-positive staining on TIMCs. Increasing CD8+ density within tumors, but not immune stroma, was significantly associated with decreased PD-L1 expression by both tumor cells and TIMCs ( P =0.0043 and P =0.0007). Patients with negative PD-L1 expression had significantly better progression-free survival ( P =0.038 and P =0.0443) and a non-statistically significant trend toward longer overall survival ( P =0.0882 and P =0.1222) compared with patients with positive PD-L1 expression., Conclusion: PD-L1 is widely expressed on the membrane of tumor cells and TIMCs in ASCCs. Its negative impact on prognosis may be due to the diminished CD8+ T cell infiltration within tumors., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Aim: The present study was to compare the effects of nicotinic acid and nicotinamide on the plasma methyl donors, choline and betaine., Methods: Thirty adult subjects were randomly divided into three groups of equal size, and orally received purified water (C group), nicotinic acid (300 mg, NA group) or nicotinamide (300 mg, NM group). Plasma nicotinamide, N 1 -methylnicotinamide, homocysteine, betaine and choline levels before and 1.5-h and 3-h post-dosing, plasma normetanephrine and metanephrine concentrations at 3-h post-dosing, and the urinary excretion of N 1 -methyl-2-pyridone-5-carboxamide during the test period were examined., Results: The level of 3-h plasma nicotinamide, N 1 -methylnicotinamide, homocysteine, the urinary excretion of N 1 -methyl-2-pyridone-5-carboxamide and pulse pressure (PP) in the NM group was 221%, 3972%, 61%, 1728% and 21.2% higher than that of the control group (P < 0.01, except homocysteine and PP P < 0.05), while the 3-h plasma betaine, normetanephrine and metanephrine level in the NM group was 24.4%, 9.4% and 11.7% lower (P < 0.05, except betaine P < 0.01), without significant difference in choline levels. Similar but less pronounced changes were observed in the NA group, with a lower level of 3-h plasma N 1 -methylnicotinamide (1.90 ± 0.20 μmol/l vs. 3.62 ± 0.27 μmol/l, P < 0.01) and homocysteine (12.85 ± 1.39 μmol/l vs. 18.08 ± 1.02 μmol/l, P < 0.05) but a higher level of betaine (27.44 ± 0.71 μmol/l vs. 23.52 ± 0.61 μmol/l, P < 0.05) than that of the NM group., Conclusion: The degradation of nicotinamide consumes more betaine than that of nicotinic acid at identical doses. This difference should be taken into consideration in niacin fortification., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Aims: The aim of the present study was to assess how genetically increased Sarcoplasmic reticulum Ca2+-ATPase (Serca2a) expression affects cardiac injury after Ischemia/Reperfusion (I/R) exposure and the related mechanisms involved., Methods and Results: Rats were subjected to Left Anterior Descending coronary artery (LAD) occlusion for 30 min followed by a 24-hour reperfusion. Cardiac function analysis revealed that cardiac function dramatically improved in Serca2a transgenic rats, (Serca2aTG) rats, compared to Wild Type (WT) rats. Serca2aTG rats developed a significantly smaller myocardial infarction size compared to those in WT group. The expression of the Bcl-2 was lower in Serca2aTG rats compared with WT rats; but, Bcl-2 expression was markedly increased in Serca2aTG rats compared with WT after I/R. In addition, Bax was markedly downregulated in Serca2aTG rats compared to WT group after I/R. Meanwhile, autophagy marker LC-3B was increased in Serca2aTG group, and p62 was only increased in WT group but not in Serca2aTG group in response to I/R. Electron microscope observation confirmed that there were more autophagosomes in Serca2aTG group than in WT rats after I/R., Conclusion: our findings demonstrated that the overexpression of Serca2a plays an important role in myocardial protection from I/R injury and postischemic functional recovery, which may be via antinecrotic, anti-apoptotic and pro-autophagy signal pathways. Our research provides solid basic data and new perspective on clinical treatment in heart failure patients with long-term over-expression of Serca2a., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Oxidative stress appears to be a central event responsible for the degeneration of dopaminergic neurons in Parkinson's disease (PD). 1-methyl-4‑phenyl-1,2,3,6-tetrahydropyridine or its toxic metabolite 1‑methyl‑4‑phenylpyridinium (MPP+) are classical widely‑used pharmacological and toxic agents to model PD; they cause the production of reactive oxygen species by inhibiting mitochondrial complex I, leading to DNA oxidative damage and subsequent neuronal death. Previous findings have suggested that proliferating cell nuclear antigen (PCNA), a critical regulatory protein for DNA repair, is involved in dopaminergic neuron damage in the MPP+‑induced PD model. The naturally occurring dithiol compound, α‑lipoic acid (ALA) has been reported to provide neuroprotection in in vitro models of PD. The molecular mechanism by which ALA reduces neuronal death in PD remains to be fully elucidated. The present study aimed to analyze the ability of ALA to protect neuronal PC12 cells from the toxicity induced by MPP+, and the molecular mechanism underlying these actions using MTT and lactate dehydrogenase cytotoxicity assays, Hoechst 33258 staining and western blot analysis. The results demonstrated that ALA efficiently increased the production of PCNA in MPP+‑treated PC12 cells. Accordingly, ALA treatment attenuated MPP+‑induced toxicity in the PC12 cells, and reduced cell apoptosis. The increase in the expression levels of PCNA by ALA in the MPP+‑treated PC12 cells appeared to be mediated by repression of the p53 protein, as the expression of p53 was increased by MPP+‑treatment and reduced by ALA. Taken together, these results indicated that ALA protected dopaminergic neurons against MPP+‑induced neurotoxicity through its ability to upregulate the DNA repair protein, PCNA, via the P53 pathway.

Previous studies of implantable cardiac resynchronization therapy plus defibrillator (CRT-D) therapy used for primary prevention of sudden cardiac death have suggested that CRT-D therapy is less effective in patients with mild heart failure and a wide QRS complex. However, the long-term benefits are variable. We performed a meta-analysis of randomized trials identified in systematic searches of MEDLINE, EMBASE, and the Cochrane Database. Three studies (3858 patients) with a mean follow-up of 66 months were included. Overall, CRT-D therapy was associated with significantly lower all-cause mortality than was implantable cardioverter defibrillator (ICD) therapy (OR, 0.78; 95 % CI, 0.63-0.96; P = 0.02; I (2) = 19 %). However, the risk of cardiac mortality was comparable between two groups (OR, 0.74; 95 % CI, 0.53-1.01; P = 0.06). CRT-D treatment was associated with a significantly lower risk of hospitalization for heart failure (OR, 0.67; 95 % CI, 0.50-0.89; P = 0.005; I (2) = 55 %). The composite outcome of all-cause mortality and hospitalization for heart failure was also markedly lower with CRT-D therapy than with ICD treatment alone (OR, 0.67; 95 % CI, 0.57-0.77; P < 0.0001; I (2) = 0 %). CRT-D therapy decreased the long-term risk of mortality and heart failure events in patients with mild heart failure with a wide QRS complex. However, long-term risk of cardiac mortality was similar between two groups. More randomized studies are needed to confirm these findings, especially in patients with NYHA class I heart failure or patients without LBBB.

Particulate fluxes of trace elements (Al, Fe, Mn, Cu, Pb, Zn, Cd and Co) in the polynya area of Prydz Bay were measured using time series sediment trap lasting from December 16th 2010 to December 16th 2011. The comparison of annual fluxes from different regions, the seasonality and sources of trace element, and their association with organic matters were investigated. The fluxes of Cu, Zn and Cd in the polynya area of Prydz Bay are dominated by marine biogenic sources. Their similar seasonality with the export of biological materials (biogenic silica, organic carbon, and calcite carbonate) is strongly related to the ice coverage and biological production. Mineral debris derived from Antarctic continent is suggested to account for the particulate fluxes of Al, Fe, Mn, Pb and Co in the polynya. Their seasonal variations are most likely controlled by ice melting and freezing process. Furthermore, their fluxes are also influenced by scavenging onto biogenic material for Pb and uptake by phytoplankton for Co. The excess fluxes of Cu, Zn and Cd have good relationship with organic carbon export. The coupling patterns are mainly regulated by source composition of trace elements and non-lithogenic input from atmospheric deposition or upwelling, and partly influenced by biological uptake process., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aims: Point-of-care genetic analysis may require polymerase chain reaction (PCR) to be carried out on whole blood. However, human blood contains natural inhibitors of PCR such as hemoglobin, immunoglobulin G, lactoferrin, and proteases, as well as anticoagulant agents, including EDTA and heparin that can reduce whole blood PCR efficiency. Our purpose was to develop a highly specific, direct whole blood single-nucleotide polymorphism (SNP) analysis method based on allele-specific (AS) PCR that is mediated by Pfu DNA polymerase and phosphorothioate-modified AS primers., Results: At high Mg(2+) concentrations, Pfu DNA polymerase efficiently amplified genomic DNA in a reaction solution containing up to 14% whole blood. Among the three anticoagulants tested, Pfu DNA polymerase showed the highest activity with sodium citrate. Meanwhile, Triton X-100 and betaine inhibited Pfu DNA polymerase activity in whole blood PCR, whereas trehalose had virtually no effect. These findings provided for the development of a low-cost, simple, and fast direct whole blood genotyping method that uses Pfu DNA polymerase combined with phosphorothioate AS primers for CYP2C9*3 and VKORC1(-1639) loci., Conclusions: With its high DNA amplification efficiency and tolerance of various blood conditions, Pfu DNA polymerase can be used in clinical laboratories to analyze SNPs in whole blood samples.

Objective: The renin-angiotensin system (RAS) and renal sympathetic nerve system (RSNS) are involved in the development of hypertension. The present study is designed to explore the possible roles of the RAS and the RSNS in foot shock-induced hypertension., Methods: Male Sprague-Dawley rats were divided into six groups: control, foot shock, RSNS denervation, denervation plus foot shock, Captopril (angiotensin I converting enzyme inhibitor, ACE inhibitor) plus foot shock, and Tempol (superoxide dismutase mimetic) plus foot shock. Rats received foot shock for 14 days. We measured the quantity of thiobarbituric acid reactive substances (TBARS), corticosterone, renin, and angiotensin II (Ang II) in plasma, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and renal noradrenaline content. RAS component mRNA and protein levels were quantified in the cerebral cortex and hypothalamus., Results: The two week foot shock treatment significantly increased systolic blood pressure, which was accompanied by an increase in angiotensinogen, renin, ACE1, and AT1a mRNA and protein expression in the cerebral cortex and hypothalamus, an increase of the plasma concentrations of renin, Ang II, corticosterone, and TBARS, as well as a decrease in plasma SOD and GSH-Px activities. Systolic blood pressure increase was suppressed by denervation of the RSNS or treatment with Captopril or Tempol. Interestingly, denervation or Tempol treatment both decreased main RAS components not only in the circulatory system, but also in the central nervous system. In addition, decreased antioxidant levels and increased TBARS and corticosterone levels were also partially restored by denervation or treatment with Tempol or Captopril., Conclusions: RAS, RSNS and oxidative stress reciprocally potentiate to play important roles in the development of foot shock-induced hypertension.

Nicotinamide adenine dinucleotide (NAD) is a crucial molecule of energy production and signal transduction processes that have been linked to ovarian cancer development. Notably, emerging evidence has led to considerable interest in the role of DNA methyltransferase 1 (DNMT1) in the initiation and progression of ovarian cancer. However, dynamic crosstalk between NAD and DNMT1 is poorly understood. Here, we show that DNMT1 levels are upregulated, along with increased NAD levels in non-BRCA1-mutated ovarian cancer cells. In contrast, DNMT1 levels are not affected by increasing NAD levels in BRCA1-mutated ovarian cancer cells. Mechanistically, BRCA1 inactivity-mediated loss of H3K9ac enrichment around the core promoter inhibits DNMT1 transcription. Consistent with this, BRCA1 levels correlate with DNMT1 levels (R = 0.534, R < 0.001) in human ovarian cancer specimens. Therefore, these results highlight a novel regulatory effect of NAD on DNMT1, and further correlate the physiological properties of NAD metabolism with DNMT1-mediated biological processes. All of this may improve our understanding of the basic molecular mechanism underlying NAD- and DNMT1-related ovarian cancer progression.

Background: This study aimed to investigate the prevalence rate of critical illness-related corticosteroid insufficiency (CIRCI) and the effect of low-dose glucocorticoid on prognosis of CIRCI in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD)., Methods: Since January 2010 to December 2012, 385 patients, who met the criteria of AECOPD, were enrolled in the Intensive Care Unit (ICU) of the First People's Hospital and Municipal Central Hospital of Xiangtan City. The AECOPD patients complicated with CIRCI screened by an adrenalcorticotrophic hormone test within 12 hours after admission to ICU were divided into a treatment group (n=32) and a control group (n=31) for a prospective, randomized and controlled clinical trial. Hydrocortisone (150 mg/d) or normal saline was injected intravenously for 7 days. The patients were followed up for 28 days after injection. The endpoint included 28-day survival time, non-shock time, ICU stay and the period of non-mechanical ventilation. The markers of inflammation C-reactive protein, tumor necrosis factor-α, interleukin 6 and procalcitonin were measured at baseline and 7 days after treatment. The variables were analyzed by Student's t test, the non-parametric statistical test, the Chi-square test or the Kaplan-Meier method with SPSS18.0 statistic software. A P value <0.05 was considered statistically significant., Results: Totally 63 patients were diagnosed with CIRCI by an adrenalcorticotrophic hormone test and the prevalence rate was 16.4%. The shock rate of the AECOPD patients complicated with CIRCI was higher than that of the AECOPD patients without CIRCI (23.8% vs. 8.7%, P<0.01). Kaplan-Meier analysis revealed that the 28-day survival time of the treatment group was obviously longer than that of the control group (P<0.05). Compared with the control group, shock-free days within 28 days was longer in the treatment group (18.2±9.5 vs. 25.8±4.1, P<0.05). Treatment with low-dose glucocorticoid obviously decreased the markers of infection and inflammation (P<0.01), such as C-reactive protein (13.2±5.5 mg/L vs. 8.3±3.1 mg/L for the control group; 13.5±5.9 mg/L vs. 5.1±2.3 mg/L for the treatment group), tumor necrosis factor-α (26.1±16.2 μg/L vs. 17.5±11.7 μg/L for the control group; 25.0±14.8 μg/L vs. 10.4±7.8 μg/L for the treatment group) and procalcitonin (3.88 μg/L vs. 2.03 μg/L for the control group; 3.77 μg/L vs. 1.26 μg/L for the treatment group). Furthermore, the markers in the treatment group decreased more obviously than those in the control group (P<0.01)., Conclusion: The prevalence rate of CIRCI was higher in the patients with AECOPD in the department of critical medicine, and low-dose glucocorticoid treatment for one week reduced the 28-day mortality, shock time and markers of infection and inflammation.

BRCA mutations are the main known hereditary factors for ovarian cancer. Notably, emerging evidence has led to considerable interest in the role of sirtuin 1 (SIRT1) in ovarian cancer development. However, dynamic crosstalk between BRCA1 and SIRT1 is poorly understood. Here, we showed that: (i) BRCA1 inactivation events (mutation, promoter methylation, or knockdown) were accompanied by decreased SIRT1 levels and increased nicotinamide adenine dinucleotide (NAD) levels and a subsequent increase in SIRT1 activity; (ii) overexpression of BRCA1 resulted in increased SIRT1 levels, an impairment in NAD synthesis, and a subsequent inhibition of SIRT1 activity; and (iii) intracellular NAD levels were largely responsible for regulating SIRT1 activity, and BRCA1 expression patterns correlated with SIRT1 levels and NAD levels correlated with SIRT1 activity in human ovarian cancer specimens. Interestingly, although BRCA1 inactivation events inhibited SIRT1 expression, they led to a substantial increase in NAD levels that enhanced NAD-related SIRT1 activity. This is a special BRCA1-mediated compensatory mechanism for the maintenance of SIRT1 function. Therefore, these results highlight a novel interaction between BRCA1 and SIRT1, which may be beneficial for the dynamic balance between BRCA1-related biologic processes and SIRT1-related energy metabolism and stress response.

Phosphatidylethanolamine N-methyltransferase (PEMT) plays a critical role in breast cancer progression. However, the epigenetic mechanism regulating PEMT transcription remains largely unknown. Here, we show that the first promoter-specific transcript 1 is the major PEMT mRNA species, and methylation of the -132 site is a key regulatory element for the PEMT gene in BRCA1-mutated breast cancer. Mechanistically, hypermethylated -132 site-mediated loss of active histone marks H3K9ac and increase of repressive histone marks H3K9me enrichment synergistically inhibited PEMT transcription. Clinicopathological data indicated that a hypermethylated -132 site was associated with histological grade (P = 0.031) and estrogen receptor status (P = 0.004); univariate survival and multivariate analyses demonstrated that lymph node metastasis was an independent and reliable prognostic factor for BRCA1-mutated breast cancer patients. Our findings imply that genetic (e.g., BRCA1 mutation) and epigenetic mechanisms (e.g., DNA methylation and histone modifications) are jointly involved in the malignant progression of PEMT-related breast cancer.

Both hereditary factors (e.g., BRCA1) and nicotinamide adenine dinucleotide (NAD)-dependent metabolic pathways are implicated in the initiation and progression of ovarian cancer. However, whether crosstalk exists between BRCA1 and NAD metabolism remains largely unknown. Here, we showed that: (i) BRCA1 inactivation events (mutation and promoter methylation) were accompanied by elevated levels of NAD; (ii) the knockdown or overexpression of BRCA1 was an effective way to induce an increase or decrease of nicotinamide phosphoribosyltransferase (Nampt)-related NAD synthesis, respectively; and (iii) BRCA1 expression patterns were inversely correlated with NAD levels in human ovarian cancer specimens. In addition, it is worth noting that: (i) NAD incubation induced increased levels of BRCA1 in a concentration-dependent manner; (ii) Nampt knockdown-mediated reduction in NAD levels was effective at inhibiting BRCA1 expression; and (iii) the overexpression of Nampt led to higher NAD levels and a subsequent increase in BRCA1 levels in primary ovarian cancer cells and A2780, HO-8910 and ES2 ovarian cancer cell lines. These results highlight a novel link between BRCA1 and NAD. Our findings imply that genetic (e.g., BRCA1 inactivation) and NAD-dependent metabolic pathways are jointly involved in the malignant progression of ovarian cancer.

BRCA mutations are the main known hereditary factor for breast cancer. Notably, poly (ADP-ribose) polymerase 1 (PARP1) expression status plays a critical role in breast cancer progression and the clinical development of PARP1 inhibitors to treat BRCA-mutated breast cancer has advanced rapidly. However, dynamic crosstalk between BRCA1 and PARP1 remains largely unknown. Here, we showed that: (i) BRCA1 inactivation events (mutation, promoter methylation, or knockdown) were accompanied by increased PARP1 and nicotinamide adenine dinucleotide (NAD) levels, and a subsequent increase in NAD-dependent PARP1 activity in MDA-MB-231 and primary breast cancer cells; (ii) the overexpression of BRCA1 resulted in decreased PARP1 and NAD levels, and a subsequent impairment in NAD-dependent PARP1 activity in MDA-MB-231 and primary breast cancer cells; and (iii) intracellular NAD levels were largely responsible for regulating PARP1 activity in breast cancer cells, and NAD levels were positively correlated with PARP1 activity in human breast cancer specimens (R = 0.647, P < 0.001). Interestingly, the high efficiency of PARP1 triggered by BRCA1 inactivation may further inhibit BRCA1 transcription by NAD depletion. These results highlight a novel interaction between BRCA1 and PARP1, which may be beneficial for the dynamic balance between BRCA1 and PARP1-related biologic processes, especially for maintaining stable DNA repair ability. All of this may improve our understanding of the basic molecular mechanism underlying BRCA1- and PARP1-related breast cancer progression.

Ecological evidence suggests that niacin (nicotinamide and nicotinic acid) fortification may be involved in the increased prevalence of obesity and type 2 diabetes, both of which are associated with insulin resistance and epigenetic changes. The purpose of the present study was to investigate nicotinamide-induced metabolic changes and their relationship with possible epigenetic changes. Male rats (5 weeks old) were fed with a basal diet (control group) or diets supplemented with 1 or 4 g/kg of nicotinamide for 8 weeks. Low-dose nicotinamide exposure increased weight gain, but high-dose one did not. The nicotinamide-treated rats had higher hepatic and renal levels of 8-hydroxy-2'-deoxyguanosine, a marker of DNA damage, and impaired glucose tolerance and insulin sensitivity when compared with the control rats. Nicotinamide supplementation increased the plasma levels of nicotinamide, N1-methylnicotinamide and choline and decreased the levels of betaine, which is associated with a decrease in global hepatic DNA methylation and uracil content in DNA. Nicotinamide had gene-specific effects on the methylation of CpG sites within the promoters and the expression of hepatic genes tested that are responsible for methyl transfer reactions (nicotinamide N-methyltransferase and DNA methyltransferase 1), for homocysteine metabolism (betaine-homocysteine S-methyltransferase, methionine synthase and cystathionine β-synthase) and for oxidative defence (catalase and tumour protein p53). It is concluded that nicotinamide-induced oxidative tissue injury, insulin resistance and disturbed methyl metabolism can lead to epigenetic changes. The present study suggests that long-term high nicotinamide intake (e.g. induced by niacin fortification) may be a risk factor for methylation- and insulin resistance-related metabolic abnormalities.

Methylation, a methyl group-consuming reaction, plays a key role in the degradation (i.e., inactivation) of monoamine neurotransmitters, including catecholamines, serotonin and histamine. Without labile methyl groups, the methylation-mediated degradation cannot take place. Although high niacin (nicotinic acid and nicotinamide) intake, which is very common nowadays, is known to deplete the body's methyl-group pool, its effect on monoamine-neurotransmitter degradation is not well understood. The aim of this article was to investigate the effect of excess nicotinamide on the levels of plasma serotonin and histamine in healthy subjects. Urine and venous blood samples were collected from nine healthy male volunteers before and after oral loading with 100 mg nicotinamide. Plasma N(1)-methylnicotinamide, urinary N(1)-methyl-2-pyridone-5-carboxamide (2-Py), and plasma betaine levels were measured by using high-performance liquid chromatography (HPLC). Plasma concentrations of choline, serotonin and histamine were measured using commercial kits. The results showed that the plasma N(1)-methylnicotinamide level and the urinary excretion of 2-Py significantly increased after oral loading with 100 mg nicotinamide, which was accompanied with a decrease in the methyl-group donor betaine. Compared with those before nicotinamide load, five-hour postload plasma serotonin and histamine levels significantly increased. These results suggest that excess nicotinamide can disturb monoamine-neurotransmitter metabolism. These findings may be of significance in understanding the etiology of monoamine-related mental diseases, such as schizophrenia and autism (a neurodevelopmental disorder).

Background: Asthma is the most common disease in children, and its pathogenesis is highly complicated., Methods: CD4+ cells and CD4+ IL-17+ cells were analysed by flow cytometry, and the ratio of CD4+ cells to the peripheral blood mononuclear cells (PBMCs) and CD4+ IL-17+ cells to PMBCs were calculated from the control group, acute group, and moderate group. The levels of protein expression of IL-6, IL-17, and IL-21 were detected by ELISA in the plasma and culture supernatants of PBMCs of the three groups. The correlations between IL-7 and IL-6, IL-7 and IL-21 were analysed in culture supernatants of PBMCs of the three groups., Results: The mean ratio of CD4+ IL-17+ cells/peripheral blood mononuclear cells (PBMCs) was 4.32% in the acute group, which was higher than in the control group and moderate group. The levels of IL-6 and IL-17 were elevated, and the levels of IL-21 were decreased in the acute group. The levels of IL-17 and IL-6 were positively correlated (r = 0.182, p = 0.03), and the levels of IL-17 and IL-21 were negatively correlated (r = -0.834, p = 0.02)., Conclusions: The results suggest that the levels of IL-17 and IL-6 are related to the severity of asthma. Furthermore, IL-17 may play a role in the development of childhood asthma.

Objective: To investigate the effect of insulin and gliclazide therapy on endoplasmic reticulum (ER) stress and insulin sensitivity in the liver of type 2 diabetic rats., Methods: A high fat diet plus a low-dose of streptozotocin was implemented to create a type 2 diabetic rats which were randomly divided into diabetes mellitus (DM) group, insulin treatment (INS) group and gliclazide treatment (GT) group; and healthy rats were as normal control group. Diabetic rats in INS and GT groups were given neutral protamine hagedorn (NPH) insulin and gliclazide respectively for 3 weeks. Protein expression levels of immunoglobulin binding protein (Bip), spliced X-box binding protein 1 (XBP-1s), phosphorylated c-Jun on serine 73 (p-c-Jun), phosphorylated insulin receptor substrate 1 on serine 307 (p-IRS-1), and glucose-6-phosphatase (G6Pase) in liver homogenate were detected by Western blotting., Results: Compared with the normal rats, Bip and XBP-1s in the DM group were up-regulated (0.28 ± 0.07 vs 0.90 ± 0.10 for Bip; 0.41 ± 0.07 vs 0.95 ± 0.07 for XBP-1s; both P < 0.01); p-c-Jun (0.59 ± 0.18 vs 1.94 ± 0.03), p-IRS-1 (1.73 ± 0.18 vs 5.32 ± 0.22) and G6Pase(0.11 ± 0.01 vs 0.45 ± 0.01) were increased (all P values < 0.01). In the INS group, all of aforementioned changes were reversed (0.90 ± 0.10 vs 0.25 ± 0.04 for Bip; 0.95 ± 0.07 vs 0.47 ± 0.01 for XBP-1s; 1.94 ± 0.03 vs 0.50 ± 0.10 for p-c-Jun; 5.32 ± 0.22 vs 1.59 ± 0.32 for p-IRS-1; 0.45 ± 0.01 vs 0.15 ± 0.02 for G6Pase, all P values < 0.01). In the GT group, all of aforementioned changes were also attenuated (0.90 ± 0.10 vs 0.53 ± 0.02 for Bip; 0.95 ± 0.07 vs 0.78 ± 0.02 for XBP-1s; 1.94 ± 0.03 vs 1.33 ± 0.11 for p-c-Jun; 5.32 ± 0.22 vs 3.13 ± 0.02 for p-IRS-1; 0.45 ± 0.01 vs 0.25 ± 0.01 for G6Pase, all P values < 0.05). Furthermore, all of aforementioned protein levels were down-regulated more obviously in the INS group comparing to the GT group (all P values < 0.01)., Conclusions: Both insulin and gliclazide therapy could relieve ER stress and c-Jun N-terminal kinase activity and improved insulin sensitivity. The effect of insulin on Bip, XBP-1s, p-c-Jun, p-IRS-1 and G6Pase protein expressions is more obvious than that of gliclazide, which indicates besides lowering glucose, insulin might have protective effects of anti-inflammation, anti-oxidative stress or stimulation of lipid redistribution.

Nicotinamide and catecholamines are both degraded by S-adenosylmethionine-dependent methylation. Whether excess nicotinamide affects the degradation of catecholamines is unknown. The aim of this study was to investigate the effect of nicotinamide on the methylation status of the body and methylation-mediated catecholamine degradation in both normotensives and hypertensives. The study was conducted in 19 normotensives and 27 hypertensives, using a nicotinamide-loading test (100 mg orally). Plasma nicotinamide, N(1)-methylnicotinamide, homocysteine (Hcy), betaine, norepinephrine, epinephrine, normetanephrine and metanephrine levels before and 5 h after nicotinamide loading were measured. Compared with normotensives, hypertensives had higher baseline (fasting) levels of plasma nicotinamide, Hcy and norepinephrine, but lower levels of plasma normetanephrine, a methylated norepinephrine derivative. Nicotinamide loading induced a significant increase in the levels of plasma N(1)-methylnicotinamide and norepinephrine, and a significant decrease in the levels of O-methylated epinephrine (metanephrine) and betaine, a major methyl donor, in both hypertensives and normotensives. Moreover, nicotinamide-loading significantly increased plasma Hcy levels, but decreased plasma normetanephrine levels in normotensives. The baseline levels of plasma epinephrine in hypertensives were similar to those of normotensives, but the post-nicotinamide-loading levels of plasma epinephrine in hypertensives were higher than those of normotensives. This study demonstrated that excess nicotinamide might deplete the labile methyl pool, increase Hcy generation and inhibit catecholamine degradation. It also revealed that hypertensives had an abnormal methylation pattern, characterized by elevated fasting plasma levels of unmethylated substrates, nicotinamide, Hcy and norepinephrine. Therefore, it seems likely that high nicotinamide intake may be involved in the pathogenesis of Hcy-related cardiovascular disease.

In total, 185 unigenes were identified from 380 clones of postnatal skeletal muscle of Hainan Black goats by suppression subtractive hybridization (SSH) technology. Most of the differentially expressed genes involved energy metabolism and muscle contraction. The expression of 19 genes was analyzed in the longissimus dorsi muscles of 2-, 6-, 12-, 24-month olds, and four gene expression patterns were found by hierarchical cluster analysis. Most genes in first expression pattern belonged to myofibrillar proteins and had higher expression levels at 2 months old; genes of the secondary expression pattern had higher expression levels at 12 months old; tropomyoain 1 (alpha) (TPM1) was classified into the third expression pattern, and its expression level showed decreases tendency as age increased. Tropomyoain 2 (beta) (TPM2) was classified into the third expression pattern, which had the opposite expression pattern against TPM1.

Background and Purpose: The aim of this study was to evaluate the anatomical changes and investigate the prevalence in intracranial aneurysm with fenestrations using magnetic resonance angiography (MRA)., Materials and Methods: Between June 2008 and October 2010, 4652 patients (aged 23-73 years) with suspected intracranial aneurysm or other cerebrovascular diseases underwent MRA examination. MRA was performed using a three-dimensional time-of-flight technique (3D-TOF) with volume rendering (VR) and maximum intensity projection reconstruction methods. The presence and location of fenestrations and aneurysms was reviewed. When fenestrations were present in combination with aneurysms, we noted the relationship of the locations. The classification of fenestration accompanied by intracranial aneurysm was divided into three types according to the anatomical relationship as follows: Type I, aneurysm adjacent to but not on a fenestration; Type II, aneurysm located on the fenestration; type III, aneurysm located at a position remote from a fenestration., Results: Among the 4652 patients examined, 409 patients were defined with 412 intracranial aneurysms, and the prevalence of aneurysms was 8.8%. One hundred and forty-one patients were identified with fenestrations; 24 of these patients were confirmed with intracranial aneurysms. Seven cases were classified as type I, three as type II and 14 as type III. The prevalence of intracranial aneurysm with fenestrations was 17.0%, with significant statistical difference compared with aneurysms unaccompanied with fenestrations (P=0.0064)., Conclusion: The anatomical relationship between fenestrations and intracranial aneurysms was visualized by MRA with VR, which displayed pathologies with sufficient clarity to enable diagnosis. Furthermore, the results of this study suggest that physicians should be alerted to the occurrence of intracranial aneurysm following the detection of fenestrations by MRA.

The development of a reliable PCR assay for genetic testing of spinocerebellar ataxia type 3. Touchdown PCR conditions were tested and different primer sets were evaluated with genomic DNA from blood sample of patients suffering from spinocerebellar ataxia type 3 (SCA3). An improved PCR assay was developed with a new set of primers and using the optimized touchdown PCR protocol. This new assay had been successfully employed in the screening of one identificated SCA3 family. Results from the present study document a simple and reliable PCR assay for genetic testing of SCA3. Strategies used in the present study may find applications in the optimization of PCR assay for triplet expansion with GC rich in the sequence context.

Objective: To explore the effect of early insulin therapy on sterol regulatory element binding protein 1 (SREBP1) pathway and lipid accumulation in liver of type 2 diabetic rats (DM)., Methods: A high-fat diet plus a low-dose of streptozotocin (STZ) was administered to the Sprague-Dawley (SD) rats to create a type 2 diabetic animal model. Then the rats were divided into 3 groups: normal control (NC), DM (untreated diabetic rats) and INS (a 3-week treatment of NPH insulin initiated from day 3 of STZ injection). Insulin was delivered daily by a 3-week subcutaneous injection (6 - 8 U/day). Liver homogenate was prepared. The protein levels of ER stress marker immunoglobulin binding protein (Bip), oxygen-regulated protein 150 (ORP150), insulin-induced gene 1 (Insig1), SREBP1 and nuclear SREBP1 (nSREBP1) were assayed by Western blot. Adipose tissue mass was measured., Results: In the DM group, ER (endoplasmic reticulum) stress marker Bip and ORP150 were up-regulated (0.67 ± 0.02 vs 0.43 ± 0.01 for Bip; 1.11 ± 0.04 vs 1.83 ± 0.03 for ORP150, P < 0.05 for both) and Insig1 decreased (0.25 ± 0.02 vs 0.80 ± 0.07, P < 0.05). And the expressions of SREBP1 and nSREBP1 were elevated (1.03 ± 0.14 vs 0.41 ± 0.01 for SREBP1; 3.63 ± 0.77 vs 0.96 ± 0.20 for nSREBP1, P < 0.05 for both) in comparison with the normal control rats. In the INS group, all aforementioned changes became attenuated or reversed (0.41 ± 0.04 vs 0.67 ± 0.02 for Bip; 1.83 ± 0.03 vs 1.11 ± 0.04 for ORP150; 0.43 ± 0.02 vs 0.25 ± 0.02 for Insig1; 0.46 ± 0.01 vs 1.03 ± 0.14 for SREBP1; 1.65 ± 0.18 vs 3.63 ± 0.77 for nSREBP1, P < 0.05 for all). Furthermore, adipose tissue mass increased (22.4 g ± 3.6 g vs 12.0 g ± 2.6 g, P < 0.05)., Conclusion: The early insulin therapy induces a fat redistribution from liver to adipose tissue. The mechanism is probably through a reduction of ER stress and a down-regulated pathway of SREBP1 in liver of diabetic rats.

Background: The global increased prevalence of obesity and diabetes occurred after the worldwide spread of B-vitamins fortification, in which whether long-term exposure to high level of B vitamins plays a role is unknown. Our aim was to examine the relationships between B-vitamins consumption and the obesity and diabetes prevalence., Methods: This population based ecological study was conducted to examine possible associations between the consumption of the B vitamins and macronutrients and the obesity and diabetes prevalence in the US population using the per capita consumption data from the US Economic Research Service and the prevalence data from the US Centers for Disease Control and Prevention., Results: The prevalences of diabetes and adult obesity were highly correlated with per capita consumption of niacin, thiamin and riboflavin with a 26-and 10-year lag, respectively (R2 = 0.952, 0.917 and 0.83 for diabetes, respectively, and R2 = 0.964, 0.975 and 0.935 for obesity, respectively). The diabetes prevalence increased with the obesity prevalence with a 16-year lag (R2 = 0.975). The relationships between the diabetes or obesity prevalence and per capita niacin consumption were similar both in different age groups and in male and female populations. The prevalence of adult obesity and diabetes was highly correlated with the grain contribution to niacin (R2 = 0.925 and 0.901, respectively), with a 10-and 26-year lag, respectively. The prevalence of obesity in US adults during 1971-2004 increased in parallel with the increase in carbohydrate consumption with a 10-year lag. The per capita energy and protein consumptions positively correlated with the obesity prevalence with a one-year lag. Moreover, there was an 11-year lag relationship between per capita energy and protein consumption and the consumption of niacin, thiamin and riboflavin (R2 = 0.932, 0.923 and 0.849 for energy, respectively, and R2 = 0.922, 0.878 and 0.787 for protein, respectively)., Conclusions: Long-term exposure to high level of the B vitamins may be involved in the increased prevalence of obesity and diabetes in the US in the past 50 years. The possible roles of B-vitamins fortification and excess niacin consumption in the increased prevalence of obesity and diabetes were discussed.

Background: Laminopathies are a group of rare genetic disorders characterized by multiple-tissue degeneration. We describe a new laminopathy with ovarian cystadenoma and explore its molecular etiology., Methods: The case is a 15-year-old girl who presents the prominent progeroid disorders, multiple system degeneration and early-onset cystadenoma of the ovary. Candidate genes including LMNA, ZMPSTE24, PPAR G, INSR and WRN were sequenced to screen for DNA variants. The mRNA and protein expression levels of LMNA were examined in primary fibroblasts. The pathophysiological events such as morphologic alterations, cell senescence, cell proliferation, apoptosis and pRb as well as p53 protein expressions were also investigated in primary fibroblasts., Results: No mutation was identified in the candidate genes screened. Nuclear abnormalities including nuclear blebs, mislocalization of lamin A/C were evident in the patient fibroblasts. Ultrastructurally, nucleus exhibited nuclear herniation and almost complete loss of peripheral heterochromatin. In addition, lamin C protein expression was markedly reduced whereas lamin A protein level was normal and no prelamin A was detected in the primary fibroblasts. Although the senescence-associated beta-galactosidase staining of patient' cells was negative, cells in S phase increased in accompany with a decrease in pRb protein expression. Furthermore, increases in apoptotic cell death and p53 expression were observed., Conclusions: Our data suggest that selective deficiency of lamin C protein is associated with a case of laminopathy with ovarian cystadenoma. The abnormalities in nuclear structure and alterations in gene expression such as the decrease in pRb and increase in p53 may be responsible for the multiple tissue degeneration.