bluuebunny/crossref_metadata_2025 huggingface dataset:
Gender and Socioeconomic Disparities in Global Burden of Epilepsy: An Analysis of Time Trends From 1990 to 2017
Authors: Hu Yin , Shan Yi , Du Qiang , Ding Yao , Shen Chunhong , Wang Shuang , Ding Meiping , Xu Yufeng
Published: April 2021

Objective: The objective of the study is to investigate the gender and socioeconomic disparities in the global burden of epilepsy by prevalence and disability-adjusted life-years (DALYs).

Methods: The global, regional, and national gender-specific prevalence and DALYs caused by epilepsy by year and age were extracted from the Global Burden of Disease (GBD) Study 2017. The Gini coefficient and concentration index (CI) were calculated to demonstrate the trends in between-country inequality in the epilepsy burden from 1990 to 2017. Paired Wilcoxon signed rank test, Pearson correlation, and linear regression analyses were performed to analyze the association of gender disparity in epilepsy and socio-demographic index (SDI).

Results: The DALYs number of epilepsies increased from 1990 to 2017 by 13.8%, whereas age-standardized DALY rates showed a substantial reduction (16.1%). Men had a higher epilepsy burden than women of the same period. The epilepsy burden appeared to be higher in countries with lower socioeconomic development (CI < 0). The Gini coefficient decreased from 0.273 in 1995 to 0.259 in 2017, representing a decline in the between-country gap. Age-standardized prevalence and DALY rates of men were higher than those of women in each SDI-based country group (p < 0.0001). Male-minus-female difference (r = −0.5100, p < 0.0001) and male-to-female ratio (r = −0.3087, p < 0.0001) of age-standardized DALY rates were negatively correlated with SDI.

Conclusion: Although global health care of epilepsy is in progress, the epilepsy burden was concentrated in males and developing countries. Our findings highlight the importance of formulating gender-sensitive health policies and providing more services in developing countries.
Development and Validation of a Clinical Prediction Model for Sleep Disorders in the ICU: A Retrospective Cohort Study
Authors: Li Yun , Zhao Lina , Yang Chenyi , Yu Zhiqiang , Song Jiannan , Zhou Qi , Zhang Xizhe , Gao Jie , Wang Qiang , Wang Haiyun
Published: April 2021

Background

Sleep disorders, the serious challenges faced by the intensive care unit (ICU) patients are important issues that need urgent attention. Despite some efforts to reduce sleep disorders with common risk-factor controlling, unidentified risk factors remain.

Objectives

This study aimed to develop and validate a risk prediction model for sleep disorders in ICU adults.

Methods

Data were retrieved from the MIMIC-III database. Matching analysis was used to match the patients with and without sleep disorders. A nomogram was developed based on the logistic regression, which was used to identify risk factors for sleep disorders. The calibration and discrimination of the nomogram were evaluated with the 1000 bootstrap resampling and receiver operating characteristic curve (ROC). Besides, the decision curve analysis (DCA) was applied to evaluate the clinical utility of the prediction model.

Results

2,082 patients were included in the analysis, 80% of whom (n = 1,666) and the remaining 20% (n = 416) were divided into the training and validation sets. After the multivariate analysis, hemoglobin, diastolic blood pressure, respiratory rate, cardiovascular disease, and delirium were the independent risk predictors for sleep disorders. The nomogram showed high sensitivity and specificity of 75.6% and 72.9% in the ROC. The threshold probability of the net benefit was between 55% and 90% in the DCA.

Conclusion

The model showed high performance in predicting sleep disorders in ICU adults, the good clinical utility of which may be a useful tool for providing clinical decision support to improve sleep quality in the ICU.
Beta-Glucan From Barley Attenuates Post-prandial Glycemic Response by Inhibiting the Activities of Glucose Transporters but Not Intestinal Brush Border Enzymes and Amylolysis of Starch
Authors: Malunga Lovemore Nkhata , Ames Nancy , Zhouyao Haonan , Blewett Heather , Thandapilly Sijo Joseph
Published: April 2021

Beta (β)-glucan (BG) from cereal grains is associated with lowering post-prandial blood glucose but the precise mechanism is not well-elucidated. The main aim of this study was to understand the mechanism through which BG from barley affects post-prandial glycemic response. Waffles containing 0, 1, 2, and 3 g barley BG and the same amount of available carbohydrate (15 g) were fed to the TIM-1 dynamic gastrointestinal digestion system to study the effect of BG on starch hydrolysis. Intestinal acetone powder and Xenopus laevis oocytes were used to study BG's effect on mammalian intestinal α-glucosidase and glucose transporters. The presence of BG did not significantly affect the in vitro starch digestion profiles of waffles suggesting that BG does not affect α-amylase activity. Intestinal α-glucosidase and glucose transport activities were significantly (p < 0.0001) inhibited in the presence of barley BG. Interestingly, BG viscosity did not influence α-amylase, α-glucosidase, GLUT2, and SGLT1 activities. This study provides the first evidence for the mechanism by which BG from barley attenuates post-prandial glycemic response is via alteration of α-glucosidase, GLUT2, and SGLT1 activity, but not amylolysis of starch. The decrease in post-prandial blood glucose in the presence of BG is likely a consequence of the interaction between BG and membrane active proteins (brush border enzymes and glucose transporters) as opposed to the commonly held hypothesis that increased viscosity caused by BG inhibits starch digestion.
Sarcopenic Obesity in Africa: A Call for Diagnostic Methods and Appropriate Interventions
Authors: Mendham Amy E. , Lundin-Olsson Lillemor , Goedecke Julia H. , Micklesfield Lisa K. , Christensen Dirk L. , Gallagher Iain J. , Myburgh Kathryn H. , Odunitan-Wayas Feyisayo A. , Lambert Estelle V. , Kalula Sebastiana , Hunter Angus M. , Brooks Naomi E.
Published: April 2021

This perspective aims to highlight the lack of current knowledge on sarcopenic obesity in Africa and to call for diagnostic methods and appropriate interventions. Sarcopenic obesity has been defined as obesity that occurs in combination with low muscle mass and function, which is typically evident in older adults. However, there has been no clear consensus on population-specific diagnostic criterion, which includes both gold-standard measures that can be used in a more advanced health care system, and surrogate measures that can be used in low-income settings with limited resources and funding. Importantly, low and middle-income countries (LMICs) across Africa are in an ongoing state of economic and social transition, which has contributed to an increase in the aging population, alongside the added burden of poverty, obesity, and associated co-morbidities. It is anticipated that alongside the increased prevalence of obesity, these countries will further experience an increase in age-related musculoskeletal diseases such as sarcopenia. The developmental origins of health and disease (DOHaD) approach will allow clinicians and researchers to consider developmental trajectories, and the influence of the environment, for targeting high-risk individuals and communities for treatment and/or prevention-based interventions that are implemented throughout all stages of the life course. Once a valid and reliable diagnostic criterion is developed, we can firstly assess the prevalence and burden of sarcopenic obesity in LMICs in Africa, and secondly, develop appropriate and sustainable interventions that target improved dietary and physical activity behaviors throughout the life course.
The Sensitivity Prediction of Neoadjuvant Chemotherapy for Gastric Cancer
Authors: Sun Juan , Wang Xianze , Zhang Zimu , Zeng Ziyang , Ouyang Siwen , Kang Weiming
Published: April 2021

The overall efficacy of neoadjuvant chemoradiotherapy (NACT) for locally advanced gastric cancer (LAGC) has been recognized. However, the response rate of NACT is limited due to tumor heterogeneity. For patients who are resistant to NACT, not only the operation timing will be postponed, patients will also suffer from the side effects of it. Thus, it is important to develop a comprehensive strategy and screen out patients who may be sensitive to NACT. This article summarizes the related research progress on the sensitivity prediction of NACT for GC in the following aspects: microRNAs, metabolic enzymes, exosomes, other biomarkers; inflammatory indicators, and imageological assessments. The results showed that there were many studies on biomarkers, but no unified conclusion has been drawn. The inflammatory indicators are related to the survival and prognosis of patients under NACT. For imageological assessments such as CT, MRI, and PET, with careful integration and optimization, they will have unique advantages in early screening for patients who are sensitive to NACT.
Identifying and Validating Potential Biomarkers of Early Stage Lung Adenocarcinoma Diagnosis and Prognosis
Authors: Chen Yingji , Jin Longyu , Jiang Zhibin , Liu Suo , Feng Wei
Published: April 2021

Background

Lung adenocarcinoma (LUAD) is the most common pathological type of lung cancer. At present, most patients with LUAD are diagnosed at an advanced stage, and the prognosis of advanced LUAD is poor. Hence, we aimed to identify novel biomarkers for the diagnosis and treatment of early stage LUAD and to explore their predictive value.

Methods

The microarray datasets GSE63459, GSE27262, and GSE33532 were searched, and the differentially expressed genes (DEGs) were obtained using GEO2R. The DEGs were subjected to gene ontology (GO) and pathway enrichment analyses using METASCAPE. A protein–protein interaction (PPI) network was plotted with STRING and visualized by Cytoscape. Module analysis of the PPI network was performed using MCODE. Overall survival (OS) analysis and analysis of the mRNA expression levels of genes identified by MCODE were performed with UALCAN. Western blot analysis of hub genes in LUAD patients, MTS assays, and clonogenic assays were performed to test the effects of the hub genes on cell proliferation in vitro.

Results

A total of 341 DEGs were obtained, which were mainly enriched in terms related to blood vessel development, growth factor binding, and extracellular matrix organization. A PPI network consisting of 300 nodes and 1140 edges was constructed, and a significant module including 15 genes was identified. Elevated expression of ASPM, CCNB2, CDCA5, PRC1, KIAA0101, and UBE2T was associated with poor OS in LUAD patients. In the protein level, the hub gene was overexpressed in LUAD patients. In vitro experiments showed that knockdown of the hub genes in the LUAD cell lines could promote cell proliferation.

Conclusions

DEGs are potential biomarkers for early stage lung adenocarcinoma and could have utility for the diagnosis and predicting treatment efficacy.
LCT-3d Induces Oxidative Stress-Mediated Apoptosis by Upregulating Death Receptor 5 in Gastric Cancer Cells
Authors: Wang Menglin , Wu Xinxin , Yu Lu , Hu Zi-yun , Li Xiaobo , Meng Xia , Lv Chun-tao , Kim Gi-Young , Choi Yung Hyun , Wang Zhengya , Xu Hai-Wei , Jin Cheng-Yun
Published: April 2021

Gastric cancer is a global health problem. In this study, we investigate the role of a novel Indole derivative, named LCT-3d, in inhibiting the growth of gastric cancer cells by MTT assay. The Western blotting results showed that LCT-3d modulated the mitochondrial-related proteins and Cleaved-Caspases 3/9, to induce cell apoptosis. The up-regulation of Death receptor 5 (DR5) in MGC803 cells was observed with LCT-3d treatment. Knockdown of DR5 on MGC803 cells partially reversed the LCT-3d-induced mitochondrial apoptosis. The level of Reactive Oxygen Species (ROS) in MGC803 cells was increased with LCT-3d treatment and could be blocked with the pretreatment of the ROS inhibitor N-Acetylcysteine (NAC). The results demonstrate that the elevating ROS can up-regulate the expression of DR5, resulting in apoptosis via mitochondrial pathway. Although the nuclear factor erythroid-2 related factor 2 (Nrf2) pathway served an important role in protecting gastric cancer cells against the injury of ROS, it can’t reverse LCT-3d-induced cell apoptosis. Taken together, our study showed that LCT-3d induced apoptosis via DR5-mediated mitochondrial apoptotic pathway in gastric cancer cells. LCT-3d could be a novel lead compound for development of anti-cancer activity in gastric cancer.
The Diarylheptanoid Curcumin Induces MYC Inhibition and Cross-Links This Oncoprotein to the Coactivator TRRAP
Authors: Mödlhammer Alexander , Pfurtscheller Sandra , Feichtner Andreas , Hartl Markus , Schneider Rainer
Published: April 2021

The c-Myc protein (MYC) is a transcription factor with strong oncogenic potential controlling fundamental cellular processes. In most human tumors, MYC is overexpressed by enhanced transcriptional activation, gene amplification, chromosomal rearrangements, or increased protein stabilization. To pharmacologically suppress oncogenic MYC functions, multiple approaches have been applied either to inhibit transcriptional activation of the endogenous MYC gene, or to interfere with biochemical functions of aberrantly activated MYC. Other critical points of attack are targeted protein modification, or destabilization leading to a non-functional MYC oncoprotein. It has been claimed that the natural compound curcumin representing the principal curcumoid of turmeric (Curcuma longa) has anticancer properties although its specificity, efficacy, and the underlying molecular mechanisms have been controversially discussed. Here, we have tested curcumin’s effect on MYC-dependent cell transformation and transcriptional activation, and found that this natural compound interferes with both of these MYC activities. Furthermore, in curcumin-treated cells, the endogenous 60-kDa MYC protein is covalently and specifically cross-linked to one of its transcriptional interaction partners, namely the 434-kDa transformation/transcription domain associated protein (TRRAP). Thereby, endogenous MYC levels are strongly reduced and cells stop to proliferate. TRRAP is a multidomain adaptor protein of the phosphoinositide 3-kinase-related kinases (PIKK) family and represents an important component of many histone acetyltransferase (HAT) complexes. TRRAP is important to mediate transcriptional activation executed by the MYC oncoprotein, but on the other hand TRRAP also negatively regulates protein stability of the tumor suppressor p53 (TP53). Curcumin-mediated covalent binding of MYC to TRRAP reduces the protein amounts of both interaction partners but does not downregulate TP53, so that the growth-arresting effect of wild type TP53 could prevail. Our results elucidate a molecular mechanism of curcumin action that specifically and irreversibly targets two crucial multifunctional cellular players. With regard to their broad impact in cancer, our findings contribute to explain the pleiotropic functions of curcumin, and suggest that this natural spice, or more bioavailable derivatives thereof, may constitute useful adjuvants in the therapy of MYC-dependent and TRRAP-associated human tumors.
Comprehensive RNA-Seq Analysis of Potential Therapeutic Targets of Gan–Dou–Fu–Mu Decoction for Treatment of Wilson Disease Using a Toxic Milk Mouse Model
Authors: Wei Taohua , Hao Wenjie , Tang Lulu , Wu Huan , Huang Shi , Yang Yue , Qian Nannan , Liu Jie , Yang Wenming , Duan Xianchun
Published: April 2021

Background: Gan–Dou–Fu–Mu decoction (GDFMD) improves liver fibrosis in experimental and clinical studies including those on toxic mouse model of Wilson disease (Model). However, the mechanisms underlying the effect of GDFMD have not been characterized. Herein, we deciphered the potential therapeutic targets of GDFMD using transcriptome analysis.

Methods: We constructed a tx-j Wilson disease (WD) mouse model, and assessed the effect of GDFMD on the liver of model mice by hematoxylin and eosin, Masson, and immunohistochemical staining. Subsequently, we identified differentially expressed genes (DEGs) that were upregulated in the Model (Model vs. control) and those that were downregulated upon GDFMD treatment (compared to the Model) using RNA-sequencing (RNA-Seq). Biological functions and signaling pathways in which the DEGs were involved were determined by gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses. A protein–protein interaction (PPI) network was constructed using the STRING database, and the modules were identified using MCODE plugin with the Cytoscape software. Several genes identified in the RNA-Seq analysis were validated by real-time quantitative PCR.

Results: Total of 2124 DEGs were screened through the Model vs. control and Model vs. GDFMD comparisons, and dozens of GO and KEGG pathway terms modulated by GDFMD were identified. Dozens of pathways involved in metabolism (including metabolic processes for organic acids, carboxylic acids, monocarboxylic acids, lipids, fatty acids, cellular lipids, steroids, alcohols, eicosanoids, long-chain fatty acids), immune and inflammatory response (such as complement and coagulation cascades, cytokine–cytokine receptor interaction, inflammatory mediator regulation of TRP channels, antigen processing and presentation, T-cell receptor signaling pathway), liver fibrosis (such as ECM-receptor interactions), and cell death (PI3K-Akt signaling pathway, apoptosis, TGF-beta signaling pathway, etc.) were identified as potential targets of GDFMD in the Model. Some hub genes and four modules were identified in the PPI network. The results of real-time quantitative PCR analysis were consistent with those of RNA-Seq analysis.

Conclusions: We performed gene expression profiling of GDFMD-treated WD model mice using RNA-Seq analysis and found the genes, pathways, and processes effected by the treatment. Our study provides a theoretical basis to prevent liver fibrosis resulting from WD using GDFMD.
MicroRNA-223 Suppresses IL-1β and TNF-α Production in Gouty Inflammation by Targeting the NLRP3 Inflammasome
Authors: Zhang Quan-Bo , Zhu Dan , Dai Fei , Huang Yu-Qin , Zheng Jian-Xiong , Tang Yi-Ping , Dong Zeng-Rong , Liao Xia , Qing Yu-Feng
Published: April 2021

Introduction: MicroRNA-223 (MiR-223) serves as an important regulator of inflammatory and immune responses and is implicated in several auto-inflammatory disorders. Here, we measured miR-223 expression in acute and intercritical gout patients, after which we used RAW264.7 macrophages transfected with a miR-223 mimic/inhibitor to determine the function of miR-223 in monosodium urate (MSU)-induced gouty inflammation.

Methods and Results: MiR-223 was detected among 122 acute gout patients (AG), 118 intercritical gout patients (IG), and 125 healthy subjects (HC). RAW264.7 macrophages were cultured and treated with MSU. Over-expression or under-expression of miR-223 was inducted in RAW264.7 macrophages to investigate the function of miR-223. Real-time quantitative PCR, ELISA and western blotting were used to determine the expression levels of miR-223, cytokines and the NLRP3 inflammasome (NLRP3, ASC, and caspase-1). MiR-223 expression was significantly decreased in the AG group in comparison with the IG and HC groups (p < 0.001, respectively). Up-regulated expression of miR-223 was observed after acute gout remission in comparison with that observed during gout flares in 30 paired cases (p < 0.001). The abundance of the NLRP3 inflammasome and cytokines was significantly increased after RAW264.7 macrophages were treated with MSU (p < 0.01, respectively), while that of miR-223 was significantly reduced (p < 0.01). Up-regulation of miR-223 decreased the concentrations of IL-1β and TNF-α, as well as the NLRP3 inflammasome expression (p < 0.01, respectively), while IL-37 and TGF-β1 levels were unchanged (p > 0.05, respectively). Under-expression of miR-223 increased the concentrations of IL-1β and TNF-α, as well as NLRP3 inflammasome expression (p < 0.01, respectively), while IL-37 and TGF-β1 levels were not influenced (p > 0.05, respectively).

Conclusion: These findings suggest that miR-223 provides negative feedback regulation of the development of gouty inflammation by suppressing production of IL-1β and TNF-α, but not by regulating IL-37 and TGF-β1. Moreover, miR-223 regulates cytokine production by targeting the NLRP3 inflammasome.
Development of an Advanced Multicellular Intestinal Model for Assessing Immunomodulatory Properties of Anti-Inflammatory Compounds
Authors: Marescotti Diego , Lo Sasso Giuseppe , Guerrera Diego , Renggli Kasper , Ruiz Castro Pedro A. , Piault Romain , Jaquet Vincent , Moine Fabian , Luettich Karsta , Frentzel Stefan , Peitsch Manuel C. , Hoeng Julia
Published: April 2021

Intestinal inflammation is the collective term for immune system-mediated diseases of unknown, multifactorial etiology, with often complex interactions between genetic and environmental factors. To mechanistically investigate the effect of treatment with compounds possessing immunomodulating properties in the context of intestinal inflammation, we developed an immunocompetentin vitrotriculture intestinal model consisting of a differentiated intestinal epithelial layer (Caco-2/HT29-MTX) and immunocompetent cells (differentiated THP-1). The triculture mimicked a healthy intestine with stable barrier integrity. Lipopolysaccharide treatment triggered a controlled and reversible inflammatory state, resulting in significant impairment of barrier integrity and release of pro-inflammatory cytokines and chemokines, which are known hallmarks of intestinal inflammation. Treatment with known anti-inflammatory reference compounds (TPCA-1 and budenoside) prevented the induction of an inflammatory state; the decreasing triculture responses to this treatment measured by cytokine release, transepithelial electric resistance (TEER), and epithelial layer permeability proved the suitability of the intestinal model for anti-inflammatory drug screening. Finally, selected tobacco alkaloids (nicotine and anatabine (R/SandSforms)) were tested in thein vitrotriculture for their potential anti-inflammatory properties. Indeed, naturally occurring alkaloids, such as tobacco-derived alkaloids, have shown substantial anti-inflammatory effects in severalin vitroandin vivomodels of inflammation, gaining increasing interest. Similar to the anti-inflammatory reference compounds, one of the tobacco alkaloids under investigation partially prevented the decrease in the TEER and increase in permeability and reduced the release of pro-inflammatory cytokines and chemokines. Taken together, these data confirm that ourin vitromodel is suitable for screening potential anti-inflammatory compounds in the context of intestinal inflammation.
Monobenzone, a Novel and Potent KDM1A Inhibitor, Suppresses Migration of Gastric Cancer Cells
Authors: Ma Peizhi , Jia Gang , Song Zhiyu
Published: April 2021

Lysine-specific demethylase1 (KDM1A) is generally highly expressed in various cancer tissues, and promotes the initiation and development of cancers via diverse cellular signaling pathways. Therefore, KDM1A is a promising drug target in many cancers, and it is crucial to find effective KDM1A inhibitors, while none of them has entered into market. With the help of compound library, monobenzone, a local depigmentor using as a treating over-pigmentation in clinic, was characterized as an effective KDM1A inhibitor (IC50 = 0.4507 μM), which may competitively inhibit KDM1A reversibly. Further cellular study confirmed that monobenzone could inhibit the proliferation of gastric cancer cell lines MGC-803 and BGC-823 with IC50 as 7.82 ± 0.55 μM and 6.99 ± 0.51 μM, respectively, and erase the substrate of KDM1A, H3K4me1/2 and H3K9 me2, and inhibit the migration of gastric cancer cell by reversing epithelial–mesenchymal transition (EMT). As the structure of monobenzone is very simple and small, this study provides a novel backbone for the further optimization of KDM1A inhibitor and gives monobenzone potential new application.
PI3K/AKT Signal Pathway: A Target of Natural Products in the Prevention and Treatment of Alzheimer’s Disease and Parkinson’s Disease
Authors: Long Hui-Zhi , Cheng Yan , Zhou Zi-Wei , Luo Hong-Yu , Wen Dan-Dan , Gao Li-Chen
Published: April 2021

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are two typical neurodegenerative diseases that increased with aging. With the emergence of aging population, the health problem and economic burden caused by the two diseases also increase. Phosphatidylinositol 3-kinases/protein kinase B (PI3K/AKT) signaling pathway regulates signal transduction and biological processes such as cell proliferation, apoptosis and metabolism. According to reports, it regulates neurotoxicity and mediates the survival of neurons through different substrates such as forkhead box protein Os (FoxOs), glycogen synthase kinase-3β (GSK-3β), and caspase-9. Accumulating evidences indicate that some natural products can play a neuroprotective role by activating PI3K/AKT pathway, providing an effective resource for the discovery of potential therapeutic drugs. This article reviews the relationship between AKT signaling pathway and AD and PD, and discusses the potential natural products based on the PI3K/AKT signaling pathway to treat two diseases in recent years, hoping to provide guidance and reference for this field. Further development of Chinese herbal medicine is needed to treat these two diseases.
Improved Survival and Retinal Function of Aging ZDF Rats in Long-Term, Uncontrolled Diabetes by BGP-15 Treatment
Authors: Wachal Zita , Szilágyi Anna , Takács Barbara , Szabó Adrienn Mónika , Priksz Dániel , Bombicz Mariann , Szilvássy Judit , Juhász Béla , Szilvássy Zoltán , Varga Balázs
Published: April 2021

Retinal complications of diabetes often lead to deterioration or even loss of vision. This hastens discovery of pharmacological agents able to counterbalance diabetic retinopathy. BGP-15, an emerging small molecule agent, was formerly proven by our workgroup to be retinoprotective on nonobese diabetic animals, Goto-Kakizaki rats. In the present study, we aimed to examine its long-term tolerability or incidental side effects on obese-prone Zucker diabetic fatty (ZDF) rats to further increase the rationale for a future human translation. To make terminal visual status comparable with our other investigations, we also carried out electroretinography (ERG) at the end of the experiment. Our study was started on 16-week-old ZDF rats and lasted for 52 weeks, while BGP was administered daily by gavage. During the 12 months of treatment, 100% of BGP-treated animals survived compared to the non-treated ZDF group, where 60% of the animals died, which was a statistically significant difference. Based on ERG results, BGP-15 was able to counterbalance visual deterioration of ZDF rats caused by long-term diabetes. Some moderate but significant changes were seen in OGTT results and some relationship to oxidative stress by the western blot method: BGP-15 was able to increase expression of HSP70 and decrease that of NFkB in eyes of rats. These were in concert with our previous observations of SIRT1 increment and MMP9 decrement in diabetic eyes by BGP. In summary, not only is BGP-15 not harmful in the long run but it is even able to reduce the related mortality and the serious consequences of diabetes. BGP-15 is an excellent candidate for future drug development against diabetic retinopathy.
Celastrol Attenuates Lipid Accumulation and Stemness of Clear Cell Renal Cell Carcinoma via CAV-1/LOX-1 Pathway
Authors: Zhang Chan-Juan , Zhu Neng , Wang Yu-Xiang , Liu Le-Ping , Zhao Tan-Jun , Wu Hong-Tao , Liao Duan-Fang , Qin Li
Published: April 2021

Clear cell renal cell carcinoma (ccRCC) is characterized by abnormal lipid accumulation. Celastrol is a pentacyclic triterpene extracted from Tripterygium wilfordii Hook F with anti-cancer activity. In the present study, the anticancer effects of celastrol on ccRCC and the underlying mechanisms were studied. Patients with reduced high density lipoprotein (HDL) and elevated levels of triglyceride (TG), total cholesterol (TC), low density lipoprotein (LDL) was found to have higher risk of ccRCC. In ccRCC clinical samples and cell lines, caveolin-1 (CAV-1) was highly expressed. CAV-1 was identified as a potential prognostic biomarker for ccRCC. Celastrol inhibited tumor growth and decreased lipid deposition promoted by high-fat diet in vivo. Celastrol reduced lipid accumulation and caveolae abundance, inhibited the binding of CAV-1 and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in ccRCC cells. Furthermore, celastrol attenuated stemness through blocking Wnt/β-catenin pathway after knockdown of CAV-1 and LOX-1. Therefore, the findings suggest that celastrol may be a promising active ingredient from traditional Chinese medicine for anti-cancer therapy.
Clozapine Metabolism is Associated With Absolute Neutrophil Count in Individuals With Treatment-Resistant Schizophrenia
Authors: Willcocks Isabella R. , Legge Sophie E. , Nalmpanti Mariana , Mazzeo Lucy , King Adrian , Jansen John , Helthuis Marinka , Owen Michael J. , O’Donovan Michael C. , Walters James T. R. , Pardiñas Antonio F.
Published: April 2021

Up to one-third of those with schizophrenia fail to respond to standard antipsychotics and are considered to have treatment-resistant schizophrenia, a condition for which clozapine is the only evidence-based medication. While up to 60% of treated individuals obtain therapeutic benefits from clozapine, it is currently underprescribed worldwide, partly because of concerns related to its broad adverse effect profile. In particular, the potential effects of clozapine on the immune system have gained relevance after a recent study showed that drug plasma concentrations were inversely correlated with neutrophil counts in individuals routinely undergoing treatment. Seeking to investigate this relationship in more detail, we extracted metabolic, immune, and genetic data from a UK cohort of long-term clozapine users linked to a clozapine monitoring service, CLOZUK2 (N = 208). Whilst a correlation analysis was compatible with the original results, a multiple linear regression accounting for dose and other confounding factors additionally allowed us to estimate the decrease in absolute neutrophil counts to approximately 141 cells/mm3 for every 0.1 mg/L increase in clozapine concentration. However, this association was attenuated after controlling for the metabolic ratio between clozapine and its main metabolite, norclozapine, which was itself negatively associated with neutrophil concentrations. Further analyses revealed that these relationships are likely moderated by genetic factors, as three pharmacogenomic SNPs previously associated to norclozapine plasma concentrations and the metabolic ratio (rs61750900, rs2011425 and rs1126545) were shown to be independently associated with a variation in neutrophil counts of about 400 cells/mm3 per effect allele. Such results are compatible with an effect of norclozapine, but not necessarily clozapine, on immune cell counts, and highlight the need for further investigations into the potential role of genetic determinants of clozapine pharmacokinetics in the occurrence of adverse effects during treatment.
Bacteroides Fragilis Polysaccharide A Ameliorates Abnormal Voriconazole Metabolism Accompanied With the Inhibition of TLR4/NF-κB Pathway
Authors: Wang Xiaokang , Ye Chunxiao , Xun Tianrong , Mo Liqian , Tong Yong , Ni Wensi , Huang Suping , Liu Bin , Zhan Xia , Yang Xixiao
Published: April 2021

The antifungal agent voriconazole (VRC) exhibits extreme inter-individual and intra-individual variation in terms of its clinical efficacy and toxicity. Inflammation, as reflected by C-reactive protein (CRP) concentrations, significantly affects the metabolic ratio and trough concentrations of voriconazole. Bacteroides fragilis (B. fragilis) is an important component of the human intestinal microbiota. Clinical data have shown that B. fragilis abundance is comparatively higher in patients not presenting with adverse drug reactions, and inflammatory cytokine (IL-1β) levels are negatively correlated with B. fragilis abundance. B. fragilis natural product capsular polysaccharide A (PSA) prevents various inflammatory disorders. We tested the hypothesis that PSA ameliorates abnormal voriconazole metabolism by inhibiting inflammation. Germ-free animals were administered PSA intragastrically for 5 days after lipopolysaccharide (LPS) stimulation. Their blood and liver tissues were collected to measure VRC concentrations. PSA administration dramatically improved the resolution phase of LPS-induced hepatic VRC metabolism and inflammatory factor secretion. It reversed inflammatory lesions and alleviated hepatic pro-inflammatory factor secretion. Both in vitro and in vivo data demonstrate that PSA reversed LPS-induced IL-1β secretion, downregulated the TLR4/NF-κB signaling pathway and upregulated CYP2C19 and P-gp. To the best of our knowledge, this study is the first to show that PSA from the probiotic B. fragilis ameliorates abnormal voriconazole metabolism by inhibiting TLR4-mediated NF-κB transcription and regulating drug metabolizing enzyme and transporter expression. Thus, PSA could serve as a clinical adjunct therapy.
Molecular Targeted Agent and Immune Checkpoint Inhibitor Co-Loaded Thermosensitive Hydrogel for Synergistic Therapy of Rectal Cancer
Authors: Zhang Huaiyu , Zhang Jiayu , Liu Yilun , Jiang Yang , Li Zhongmin
Published: April 2021

Molecular targeted therapy has been proved effective in treatment of rectal cancer. Up-regulated expression of programmed death ligand-1 (PD-L1) was observed after the management of molecular targeted therapy, which made the therapeutic effect discounted. Tumors with higher PD-L1 expression were more sensitive and responsive to treatment of PD-L1 inhibitor. Therefore, the combination of molecular targeted therapy and immune checkpoint blockade makes sense. In this study, the copolymers of poly (ethylene glycol)-block-poly (L-leucine) (PEG-PLLeu) were synthesized as a thermosensitive hydrogel composite for consecutive release of regorafenib (REG) and BMS202. The mechanical properties of PEG-PLLeu were investigated, confirming that PEG-PLLeu (5 wt.%) was suitable for in situ injection as drug-delivery composite at low temperature and stable after sol-gel transition at body temperature. Importantly, the double drug loaded hydrogel showed superior antitumour activity over single drugs in an orthotopic rectal cancer model (CT26-Luc). Further analysis of the tumor tissues suggested that REG upregulated the expression of PD-L1 in tumor tissues. In addition, the immunosuppressive tumor microenvironment of CT26-Luc tumor was distinctly relieved under the effect of BMS202, as characterized by increased infiltration of CD8+ T cells in tumors and enhanced secretion of antitumour cytokines (IFN-γ and TNF-α). Moreover, the drug-loaded composite showed no obvious toxicity in histological analysis. Taken together, the administration of REG and BMS202 in the PEG-PLLeu composite could induce a synergistic effect in in situ treatment of rectal cancer without obvious toxicity, and thus represented a potential strategy for enhanced in situ therapeutic modality.
Renormalization Group Approach to the Continuum Limit of Matrix Models of Quantum Gravity With Preferred Foliation
Authors: Castro Alicia , Koslowski Tim Andreas
Published: April 2021

This contribution is not intended as a review but, by suggestion of the editors, as a glimpse ahead into the realm of dually weighted tensor models for quantum gravity. This class of models allows one to consider a wider class of quantum gravity models, in particular one can formulate state sum models of spacetime with an intrinsic notion of foliation. The simplest one of these models is the one proposed by Benedetti and Henson [1], which is a matrix model formulation of two-dimensional Causal Dynamical Triangulations (CDT). In this paper we apply the Functional Renormalization Group Equation (FRGE) to the Benedetti-Henson model with the purpose of investigating the possible continuum limits of this class of models. Possible continuum limits appear in this FRGE approach as fixed points of the renormalization group flow where the size of the matrix acts as the renormalization scale. Considering very small truncations, we find fixed points that are compatible with analytically known results for CDT in two dimensions. By studying the scheme dependence of our results we find that precision results require larger truncations than the ones considered in the present work. We conclude that our work suggests that the FRGE is a useful exploratory tool for dually weighted matrix models. We thus expect that the FRGE will be a useful exploratory tool for the investigation of dually weighted tensor models for CDT in higher dimensions.
Spontaneous Pattern Growth on Chocolate Surface: Simulations and Experiments
Authors: Delgado Jorge , Ferreiro-Córdova Claudia , Gil-Villegas Alejandro
Published: April 2021

The natural variation of temperature at ambient conditions produces spontaneous patterns on the surface of chocolate, which result from fat bloom. These metastable patterns are peculiar because of their shape and cannot be obtained by controlled temperature conditions. The formation of these spontaneous grains on the surface of chocolate is studied on experimental and theoretical grounds.Three different kinds of experiments were conducted: observation of formed patterns in time, atomic force microscopy of the initial events on the grain formation and rheology of the melted chocolate. The patterns observed in our experiments follow the trends described by the Avrami model, which considers a constant value at all spatial scales of the rate of linear growth α that governs the formation of isolated grains, starting from molecular clusters. Through NVT-ensemble computer simulations, using a Mie-segmented coarse-grained model of triacylglycerides molecules, we studied the process of nucleation that starts the pattern growth. From simulation and experiment results it is possible to derive a realistic value of α.
Infection Percolation: A Dynamic Network Model of Disease Spreading
Authors: Browne Christopher A. , Amchin Daniel B. , Schneider Joanna , Datta Sujit S.
Published: April 2021

Models of disease spreading are critical for predicting infection growth in a population and evaluating public health policies. However, standard models typically represent the dynamics of disease transmission between individuals using macroscopic parameters that do not accurately represent person-to-person variability. To address this issue, we present a dynamic network model that provides a straightforward way to incorporate both disease transmission dynamics at the individual scale as well as the full spatiotemporal history of infection at the population scale. We find that disease spreads through a social network as a traveling wave of infection, followed by a traveling wave of recovery, with the onset and dynamics of spreading determined by the interplay between disease transmission and recovery. We use these insights to develop a scaling theory that predicts the dynamics of infection for diverse diseases and populations. Furthermore, we show how spatial heterogeneities in susceptibility to infection can either exacerbate or quell the spread of disease, depending on its infectivity. Ultimately, our dynamic network approach provides a simple way to model disease spreading that unifies previous findings and can be generalized to diverse diseases, containment strategies, seasonal conditions, and community structures.
Influence of Exposure at Different Altitudes on the Executive Function of Plateau Soldiers—Evidence From ERPs and Neural Oscillations
Authors: Wei Xin , Ni Xiaoli , Zhao Shanguang , Chi Aiping
Published: April 2021

This study investigates the changes in soldiers' brain executive function at different altitude environments and their relationship with blood oxygen saturation. Stratified sampling was conducted in different altitude 133 active-duty soldiers who were stationed in Weinan (347 m, n = 34), Nyingchi (2,950 m, n = 32), Lhasa (3,860 m, n = 33), and Nagqu (4,890 m, n = 34) for 2 years. The Go/NoGo paradigm with event-related potentials (ERPs) and event-related oscillations (EROs) was used to explore the time and neural oscillation courses of response inhibition. Behavioral results revealed that at the 4,890-m altitude area, the soldiers had the highest false alarm rate, the longest reaction time, and the slowest information transmission rate. The electrophysiological results revealed that NoGo-N2 and N2d decreased with increasing altitude, with significant changes at 3,860 m; the amplitudes of NoGo-P3 and P3d in plateau groups were significantly more negative than the plain and changed significantly at 2,950 m. The results of correlation analysis showed that NoGo-P3 was negatively correlated with altitude (r = −0.358, p = 0.000), positively correlated with SpO2 (r = 0.197, p = 0.041) and information translation rate (ITR) (r = 0.202, p = 0.036). P3d was negatively correlated with altitude (r = −0.276, p = 0.004) and positively correlated with ITR (r = 0.228, p = 0.018). N2d was negatively correlated with ITR (r = 0.204, p = 0.034). The power spectrum analysis of NoGo-N2 and NoGo-P3 showed that the power of δ and θ bands at the plateau area was significantly lower than the plain area and showed a significant step-by-step decrease; the α-band power increases significantly only in the area of 4,890 m. The effect of chronic hypoxia exposure at different altitudes of the plateau on the response inhibition of soldiers was manifested: 3,860 m was the altitude at which the brain response inhibition function decreased during the conflict monitoring stage, and 2,950 m was the altitude at which it dropped during the response inhibition stage. In addition, the soldier's brain's executive function was closely related to SpO2, and a reduction in SpO2 may lead to a decline in response inhibition.
The Oncogene Transcription Factor EB Regulates Vascular Functions
Authors: Doronzo Gabriella , Astanina Elena , Bussolino Federico
Published: April 2021

Transcription factor EB (TFEB) represents an emerging player in vascular biology. It belongs to the bHLH-leucine zipper transcription factor microphthalmia family, which includes microphthalmia-associated transcription factor, transcription factor E3 and transcription factor EC, and is known to be deregulated in cancer. The canonical transcriptional pathway orchestrated by TFEB adapts cells to stress in all kinds of tissues by supporting lysosomal and autophagosome biogenesis. However, emerging findings highlight that TFEB activates other genetic programs involved in cell proliferation, metabolism, inflammation and immunity. Here, we first summarize the general principles and mechanisms by which TFEB activates its transcriptional program. Then, we analyze the current knowledge of TFEB in the vascular system, placing particular emphasis on its regulatory role in angiogenesis and on the involvement of the vascular unit in inflammation and atherosclerosis.
Biotic Yield Losses in the Southern Amazon, Brazil: Making Use of Smartphone-Assisted Plant Disease Diagnosis Data
Authors: Hampf Anna C. , Nendel Claas , Strey Simone , Strey Robert
Published: April 2021

Pathogens and animal pests (P&A) are a major threat to global food security as they directly affect the quantity and quality of food. The Southern Amazon, Brazil’s largest domestic region for soybean, maize and cotton production, is particularly vulnerable to the outbreak of P&A due to its (sub)tropical climate and intensive farming systems. However, little is known about the spatial distribution of P&A and the related yield losses. Machine learning approaches for the automated recognition of plant diseases can help to overcome this research gap. The main objectives of this study are to (1) evaluate the performance of Convolutional Neural Networks (ConvNets) in classifying P&A, (2) map the spatial distribution of P&A in the Southern Amazon, and (3) quantify perceived yield and economic losses for the main soybean and maize P&A. The objectives were addressed by making use of data collected with the smartphone application Plantix. The core of the app’s functioning is the automated recognition of plant diseases via ConvNets. Data on expected yield losses were gathered through a short survey included in an “expert” version of the application, which was distributed among agronomists. Between 2016 and 2020, Plantix users collected approximately 78,000 georeferenced P&A images in the Southern Amazon. The study results indicate a high performance of the trained ConvNets in classifying 420 different crop-disease combinations. Spatial distribution maps and expert-based yield loss estimates indicate that maize rust, bacterial stalk rot and the fall armyworm are among the most severe maize P&A, whereas soybean is mainly affected by P&A like anthracnose, downy mildew, frogeye leaf spot, stink bugs and brown spot. Perceived soybean and maize yield losses amount to 12 and 16%, respectively, resulting in annual yield losses of approximately 3.75 million tonnes for each crop and economic losses of US$2 billion for both crops together. The high level of accuracy of the trained ConvNets, when paired with widespread use from following a citizen-science approach, results in a data source that will shed new light on yield loss estimates, e.g., for the analysis of yield gaps and the development of measures to minimise them.
The Development of Mindful-Based Dance Movement Therapy Intervention for Chronic Pain: A Pilot Study With Chronic Headache Patients
Authors: Majore-Dusele Indra , Karkou Vicky , Millere Inga
Published: April 2021

Chronic pain is of significant global concern. There is growing evidence that body–mind therapies and psychological approaches can contribute toward changing chronic pain perceptions. This is the first model described in the literature that combines a mindfulness-based approach with dance movement therapy and explores the potential psychological and pain-related changes for this client population. In this paper, the results from the pilot study are presented involving patients with chronic headache recruited in an outpatient rehabilitation setting.

Methods:In this pilot study, 29 patients (n= 29) with chronic headache were randomized to either the Mindful-Based Dance Movement Therapy (MBDMT) group or the waiting list control group (treatment as usual, TAU). The MBDMT group was offered 10 sessions in a clinical outpatient rehabilitation setting for 5 weeks. Data were collected pre- and post-intervention and 16 weeks after the intervention was finished. The Hospital Anxiety and Depression Scale (HADS), Patient Health Questionnaire−9 (PHQ-9), Five Facet Mindfulness Questionnaire (FFMQ), and Numeric Rating Scale (NRS) were used as outcome measures.

Results:The working model of MBDMT identifies nine therapeutic mechanisms (safe therapeutic environment, mindfulness skills, body awareness, relaxation/releasing, distancing and staying with discomfort, meaning making, self-regulation, acceptance and integration, creative process). Per-protocol analysis reveals statistically significant reduction of pain intensity and depression scores in favor of the MBDMT group, and these improvements were maintained in the follow-up assessment.

Conclusions:The results suggest that MBDMT is a feasible and promising therapy approach for chronic pain patients. The pilot study offered sufficient information and preliminary results in the desirable direction to enable the researchers to move to a randomized controlled trial (RCT) stage in order to establish the efficacy of the intervention.

Clinical Trial Registration:The study was registered in thewww.researchregistry.com, registry (5483).