bluuebunny/crossref_metadata_2025 huggingface dataset:
NCOA4-Mediated Ferritinophagy: A Vicious Culprit in COVID-19 Pathogenesis?
Authors: Jia Fengju , Liu Hongxia , Kang Shan
Published: December 2021

Coronavirus disease 2019 (COVID-19) is a global pandemic that has caused widespread loss of life. Notably, in this disease, severe inflammatory reactions characterized by cytokine storms are caused by severe acute respiratory syndrome coronavirus 2. The cytokine storms may promote hyper-ferritinemia which can further intensify the inflammation. Moreover, elevated ferritin levels trigger nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy, in which ferritin is degraded and iron is released. Excess iron released from ferritinophagy can promote ferroptosis and cellular damage. Therefore, we propose that NCOA4-mediated ferritinophagy can be targeted to limit the ferroptosis and prevent the multi-organ damage and severity in COVID-19 patients.
Flavones 7,8-DHF, Quercetin, and Apigenin Against Tau Toxicity via Activation of TRKB Signaling in ΔK280 TauRD-DsRed SH-SY5Y Cells
Authors: Chiang Ni-Ni , Lin Te-Hsien , Teng Yu-Shan , Sun Ying-Chieh , Chang Kuo-Hsuan , Lin Chung-Yin , Hsieh-Li Hsiu Mei , Su Ming-Tsan , Chen Chiung-Mei , Lee-Chen Guey-Jen
Published: December 2021

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with memory loss and cognitive decline. Neurofibrillary tangles (NFTs) formed by hyperphosphorylated Tau protein are one of the pathological hallmarks of several neurodegenerative diseases including AD. Heat shock protein family B (small) member 1 (HSPB1) is a molecular chaperone that promotes the correct folding of other proteins in response to environmental stress. Nuclear factor erythroid 2-like 2 (NRF2), a redox-regulated transcription factor, is the master regulator of the cellular response to excess reactive oxygen species. Tropomyosin-related kinase B (TRKB) is a membrane-bound receptor that, upon binding brain-derived neurotrophic factor (BDNF), phosphorylates itself to initiate downstream signaling for neuronal survival and axonal growth. In this study, four natural flavones such as 7,8-dihydroxyflavone (7,8-DHF), wogonin, quercetin, and apigenin were evaluated for Tau aggregation inhibitory activity and neuroprotection in SH-SY5Y neuroblastoma. Among the tested flavones, 7,8-DHF, quercetin, and apigenin reduced Tau aggregation, oxidative stress, and caspase-1 activity as well as improved neurite outgrowth in SH-SY5Y cells expressing ΔK280 TauRD-DsRed folding reporter. Treatments with 7,8-DHF, quercetin, and apigenin rescued the reduced HSPB1 and NRF2 and activated TRKB-mediated extracellular signal-regulated kinase (ERK) signaling to upregulate cAMP-response element binding protein (CREB) and its downstream antiapoptotic BCL2 apoptosis regulator (BCL2). Knockdown of TRKB attenuated the neuroprotective effects of these three flavones. Our results suggest 7,8-DHF, quercetin, and apigenin targeting HSPB1, NRF2, and TRKB to reduce Tau aggregation and protect cells against Tau neurotoxicity and may provide new treatment strategies for AD.
Deep Learning With 18F-Fluorodeoxyglucose-PET Gives Valid Diagnoses for the Uncertain Cases in Memory Impairment of Alzheimer’s Disease
Authors: Zhang Wei , Zhang Tianhao , Pan Tingting , Zhao Shilun , Nie Binbin , Liu Hua , Shan Baoci ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2021

Objectives:Neuropsychological tests are an important basis for the memory impairment diagnosis in Alzheimer’s disease (AD). However, multiple memory tests might be conflicting within-subjects and lead to uncertain diagnoses in some cases. This study proposed a framework to diagnose the uncertain cases of memory impairment.

Methods:We collected 2,386 samples including AD, mild cognitive impairment (MCI), and cognitive normal (CN) using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and three different neuropsychological tests (Mini-Mental State Examination, Alzheimer’s Disease Assessment Scale-Cognitive Subscale, and Clinical Dementia Rating) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). A deep learning (DL) framework using FDG-PET was proposed to diagnose uncertain memory impairment cases that were conflicting between tests. Subsequent ANOVA, chi-squared, andt-test were used to explain the potential causes of uncertain cases.

Results:For certain cases in the testing set, the proposed DL framework outperformed other methods with 95.65% accuracy. For the uncertain cases, its positive diagnoses had a significant (p< 0.001) worse decline in memory function than negative diagnoses in a longitudinal study of 40 months on average. In the memory-impaired group, uncertain cases were mainly explained by an AD metabolism pattern but mild in extent (p< 0.05). In the healthy group, uncertain cases were mainly explained by a non-energetic mental state (p< 0.001) measured using a global deterioration scale (GDS), with a significant depression-related metabolism pattern detected (p< 0.05).

Conclusion:A DL framework for diagnosing uncertain cases of memory impairment is proposed. Proved by longitudinal tracing of its diagnoses, it showed clinical validity and had application potential. Its valid diagnoses also provided evidence and explanation of uncertain cases based on the neurodegeneration and depression mental state.
Epigenetic Age Acceleration and Hearing: Observations From the Baltimore Longitudinal Study of Aging
Authors: Kuo Pei-Lun , Moore Ann Zenobia , Lin Frank R. , Ferrucci Luigi
Published: December 2021

Objectives: Age-related hearing loss (ARHL) is highly prevalent among older adults, but the potential mechanisms and predictive markers for ARHL are lacking. Epigenetic age acceleration has been shown to be predictive of many age-associated diseases and mortality. However, the association between epigenetic age acceleration and hearing remains unknown. Our study aims to investigate the relationship between epigenetic age acceleration and audiometric hearing in the Baltimore Longitudinal Study of Aging (BLSA).

Methods: Participants with both DNA methylation and audiometric hearing measurements were included. The main independent variables are epigenetic age acceleration measures, including intrinsic epigenetic age acceleration—“IEAA,” Hannum age acceleration—“AgeAccelerationResidualHannum,” PhenoAge acceleration—“AgeAccelPheno,” GrimAge acceleration—“AgeAccelGrim,” and methylation-based pace of aging estimation—“DunedinPoAm.” The main dependent variable is speech-frequency pure tone average. Linear regression was used to assess the association between epigenetic age acceleration and hearing.

Results: Among the 236 participants (52.5% female), after adjusting for age, sex, race, time difference between measurements, cardiovascular factors, and smoking history, the effect sizes were 0.11 995% CI: (–0.00, 0.23), p = 0.054] for Hannum’s clock, 0.08 [95% CI: (–0.03, 0.19), p = 0.143] for Horvath’s clock, 0.10 [95% CI: (–0.01, 0.21), p = 0.089] for PhenoAge, 0.20 [95% CI: (0.06, 0.33), p = 0.004] for GrimAge, and 0.21 [95% CI: (0.09, 0.33), p = 0.001] for DunedinPoAm.

Discussion: The present study suggests that some epigenetic age acceleration measurements are associated with hearing. Future research is needed to study the potential subclinical cardiovascular causes of hearing and to investigate the longitudinal relationship between DNA methylation and hearing.
Sex-Specific Brain Responses to Imaginary Dance but Not Physical Dance: An Electroencephalography Study of Functional Connectivity and Electrical Brain Activity
Authors: Wind Johanna , Horst Fabian , Rizzi Nikolas , John Alexander , Kurti Tamara , Schöllhorn Wolfgang I.
Published: December 2021

To date, most neurophysiological dance research has been conducted exclusively with female participants in observational studies (i.e., participants observe or imagine a dance choreography). In this regard, the sex-specific acute neurophysiological effect of physically executed dance can be considered a widely unexplored field of research. This study examines the acute impact of a modern jazz dance choreography on brain activity and functional connectivity using electroencephalography (EEG). In a within-subject design, 11 female and 11 male participants were examined under four test conditions: physically dancing the choreography with and without music and imagining the choreography with and without music. Prior to the EEG measurements, the participants acquired the choreography over 3 weeks with one session per week. Subsequently, the participants conducted all four test conditions in a randomized order on a single day, with the EEG measurements taken before and after each condition. Differences between the male and female participants were established in brain activity and functional connectivity analyses under the condition of imagined dance without music. No statistical differences between sexes were found in the other three conditions (physically executed dance with and without music as well as imagined dance with music). Physically dancing and music seem to have sex-independent effects on the human brain. However, thinking of dance without music seems to be rather sex-specific. The results point to a promising approach to decipher sex-specific differences in the use of dance or music. This approach could further be used to achieve a more group-specific or even more individualized and situationally adapted use of dance interventions, e.g., in the context of sports, physical education, or therapy. The extent to which the identified differences are due to culturally specific attitudes in the sex-specific contact with dance and music needs to be clarified in future research.
ATPase Inhibitory Factor 1 Is Critical for Regulating Sevoflurane-Induced Microglial Inflammatory Responses and Caspase-3 Activation
Authors: Xu Yaru , Gao Ge , Sun Xiaoru , Liu Qidong , Li Cheng
Published: December 2021

Postoperative delirium (POD) is one of the most important complications after surgery with general anesthesia, for which the neurotoxicity of general anesthetics is a high-risk factor. However, the mechanism remains largely unknown, which also hinders the effective treatment of POD. Here, we confirmed that a clinical concentration of the general anesthetic sevoflurane increased the expression of inflammatory factors and activated the caspase-3 by upregulating ATPase inhibitory factor 1 (ATPIF1) expression in microglia. Upregulation of ATPIF1 decreased the synthesis of ATP which is an important signaling molecule secreted by microglia. Extracellular supplementation with ATP attenuated the microglial inflammatory response and caspase-3 activation caused by sevoflurane or overexpression of ATPIF1. Additionally, the microglial inflammatory response further upregulated ATPIF1 expression, resulting in a positive feedback loop. Animal experiments further indicated that intraperitoneal injection of ATP significantly alleviated sevoflurane anesthesia-induced POD-related anxiety behavior and memory damage in mice. This study reveals that ATPIF1, an important protein regulating ATP synthesis, mediates sevoflurane-induced neurotoxicity in microglia. ATP supplementation may be a potential clinical treatment to alleviate sevoflurane-induced POD.
Aberrant Dynamics of Regional Coherence Measured by Resting-State fMRI in Children With Benign Epilepsy With Centrotemporal Spikes (BECTS)
Authors: Jiang Lin , Ma Xuejin , Liu Heng , Wang Ji , Zhang Jiaren , Zhang Guoming , Li Shiguang , Zhang Tijiang
Published: December 2021

Objective:To explore the dynamic features of intrinsic brain activity measured by fMRI in children with benign epilepsy with centrotemporal spikes (BECTS) and examine whether these indexes were associated with behaviors.

Methods:We recruited 26 children with BECTS (10.35 ± 2.91 years) and 26 sex-, and age-matched (11.35 ± 2.51 years) healthy controls (HC) and acquired resting-state functional magnetic resonance imaging (rs-fMRI) and behavioral data. Dynamic regional homogeneity (dReHo), including mean and coefficient of variation (CV) metrics derived from the rs-fMRI data, and were compared between the BECTS and the HC groups.

Results:Significantly decreased mean dReHo in bilateral supramarginal gyrus, left middle temporal gyrus (MTG.L), left postcentral gyrus and superior occipital gyrus were found in children with BECTS. Meanwhile, increased CV of dReHo in MTG.L and right fusiform in children with BECTS was revealed compared with HC. Further analyses of functional connectivity revealed decreased global signal FC existed in similar regions, linked with linguistic, social cognition, and sensorimotor processes, in children with BECTS compared with HCs. Moreover, the association analyses showed that the CV of dReHo in MTG.L was positively associated with age and a negative correlation was found between mean dReHo of MTG.L and disease duration. Besides, the CV of dReHo in MTG.L was found positively associated with the intelligence quotient (IQ) language scores and full IQ scores in children with BECTS, and the CV of dReHo in the left inferior temporal gyrus and Rolandic operculum were positively correlated with IQ operation scores and full IQ scores.

Conclusion:Aberrant dynamic regional coherence in sensorimotor, linguistic, and lateral temporal regions suggests dynamical interplay that underlying cognitive performance in children with BECTS, suggesting an intrinsic dynamic mechanism for BECTS.
Potential Locations for Non-Invasive Brain Stimulation in Treating Schizophrenia: A Resting-State Functional Connectivity Analysis
Authors: Ning Yanzhe , Zheng Sisi , Feng Sitong , Zhang Binlong , Jia Hongxiao
Published: December 2021

Introduction: Non-invasive brain stimulation (NIBS) techniques have been widely used for the purpose of improving clinical symptoms of schizophrenia. However, the ambiguous stimulation targets may limit the efficacy of NIBS for schizophrenia. Exploring effective stimulation targets may improve the clinical efficacy of NIBS in schizophrenia.

Methods: We first conducted a neurosynth-based meta-analysis of 715 functional magnetic resonance imaging studies to identify schizophrenia-related brain regions as regions of interest. Then, we performed the resting-state functional connectivity analysis in 32 patients with first-episode schizophrenia to find brain surface regions correlated with the regions of interest in three pipelines. Finally, the 10–20 system coordinates corresponding to the brain surface regions were considered as potential targets for NIBS.

Results: We identified several potential targets of NIBS, including the bilateral dorsal lateral prefrontal cortex, supplementary motor area, bilateral inferior parietal lobule, temporal pole, medial prefrontal cortex, precuneus, superior and middle temporal gyrus, and superior and middle occipital gyrus. Notably, the 10-20 system location of the bilateral dorsal lateral prefrontal cortex was posterior to F3 (F4), not F3 (F4).

Conclusion: Conclusively, our findings suggested that the stimulation locations corresponding to these potential targets might help clinicians optimize the application of NIBS therapy in individuals with schizophrenia.
Submaximal Exercise Provokes Increased Activation of the Anterior Default Mode Network During the Resting State as a Biomarker of Postexertional Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Authors: Rayhan Rakib U. , Baraniuk James N.
Published: December 2021

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by disabling fatigue and postexertional malaise. We developed a provocation paradigm with two submaximal bicycle exercise stress tests on consecutive days bracketed by magnetic resonance imaging, orthostatic intolerance, and symptom assessments before and after exercise in order to induce objective changes of exercise induced symptom exacerbation and cognitive dysfunction.

Method: Blood oxygenation level dependent (BOLD) scans were performed while at rest on the preexercise and postexercise days in 34 ME/CFS and 24 control subjects. Seed regions from the FSL data library with significant BOLD signals were nodes that clustered into networks using independent component analysis. Differences in signal amplitudes between groups on pre- and post-exercise days were determined by general linear model and ANOVA.

Results: The most striking exercise-induced effect in ME/CFS was the increased spontaneous activity in the medial prefrontal cortex that is the anterior node of the Default Mode Network (DMN). In contrast, this region had decreased activation for controls. Overall, controls had higher BOLD signals suggesting reduced global cerebral blood flow in ME/CFS.

Conclusion: The dynamic increase in activation of the anterior DMN node after exercise may be a biomarker of postexertional malaise and symptom exacerbation in CFS. The specificity of this postexertional finding in ME/CFS can now be assessed by comparison to post-COVID fatigue, Gulf War Illness, fibromyalgia, chronic idiopathic fatigue, and fatigue in systemic medical and psychiatric diseases.
Altering Cell-Cell Interaction in Prenatal Alcohol Exposure Models: Insight on Cell-Adhesion Molecules During Brain Development
Authors: Licheri Valentina , Brigman Jonathan L.
Published: December 2021

Alcohol exposure during pregnancy disrupts the development of the brain and produces long lasting behavioral and cognitive impairments collectively known as Fetal Alcohol Spectrum Disorders (FASDs). FASDs are characterized by alterations in learning, working memory, social behavior and executive function. A large body of literature using preclinical prenatal alcohol exposure models reports alcohol-induced changes in architecture and activity in specific brain regions affecting cognition. While multiple putative mechanisms of alcohol’s long-lasting effects on morphology and behavior have been investigated, an area that has received less attention is the effect of alcohol on cell adhesion molecules (CAMs). The embryo/fetal development represents a crucial period for Central Nervous System (CNS) development during which the cell-cell interaction plays an important role. CAMs play a critical role in neuronal migration and differentiation, synaptic organization and function which may be disrupted by alcohol. In this review, we summarize the physiological structure and role of CAMs involved in brain development, review the current literature on prenatal alcohol exposure effects on CAM function in different experimental models and pinpoint areas needed for future study to better understand how CAMs may mediate the morphological, sensory and behavioral outcomes in FASDs.
Factors Associated With Dietary Quality During Initial and Later Stages of the COVID-19 Pandemic in Mexico
Authors: Batis Carolina , Irizarry Laura , Castellanos-Gutiérrez Analí , Aburto Tania C. , Rodríguez-Ramírez Sonia , Stern Dalia , Mejía Carla , Bonvecchio Anabelle
Published: December 2021

Background: The COVID-19 pandemic disrupted the global economy and modified lifestyles. The aim of our study was to identify factors associated with dietary quality, and their frequency, in Mexican adults at the initial and later stages of the pandemic.

Methods: Two online surveys were conducted between June and July 2020 (n = 3,131) and between November and December 2020 (n = 1,703 including non-participants from 1st round). A diet quality score was estimated using a short instrument to measure the consumption of several healthy/unhealthy food items. Linear regression models were used to identify the association between pandemic related factors and the diet quality score, adjusted by sociodemographic characteristics. The 2nd round was weighted to represent the 1st round.

Results: During the 1st and 2nd rounds only ~12% of the sample perceived that their intake of healthy food decreased, relative to before the pandemic; ~20% perceived that their intake of unhealthy foods increased. Diet quality remained similar between the 1st and 2nd round. The following factors were negatively associated with diet quality: Eating food prepared away-from-home; going out to work ≥4 times/week; decreased time for food preparation; decreased interest in eating healthy; eating more due to anxiety, depression, or boredom; food insecurity; and stockpiling junk food. Purchasing food using a mixed modality of both in-store and home delivery was positively associated with diet quality. With the exception of eating more due to anxiety (reported by 47% of participants), all these factors were reported by a minority of participants during the first round (≤15%). During the 2nd round, there was an increase in the frequency of participants who reported eating food prepared away-from-home, going out to work ≥4 times/week, having less time to prepare food, being more interested in eating healthfully, and a decrease in participants eating more due to anxiety, depression or boredom, or stockpiling junk food.

Conclusions: Most participants perceived that their dietary intake improved during both initial and later stages of the pandemic. This might be related to factors associated with higher dietary quality, such as not going out to work, eating homemade food, and online grocery shopping.
A Meta-Analysis of Microbial Therapy Against Metabolic Syndrome: Evidence From Randomized Controlled Trials
Authors: Pan Binhui , Liu Xiujie , Shi Jiangmin , Chen Yaoxuan , Xu Zhihua , Shi Dibang , Ruan Gaoyi , Wang Fangyan , Huang Yingpeng , Xu Changlong
Published: December 2021

Background and aims: Metabolic syndrome (MetS), accompanied with significant intestinal dysbiosis, causes a great public health burden to human society. Here, we carried out a meta-analysis to qualify randomized controlled trials (RCTs) and to systematically evaluate the effect of microbial therapy on MetS.

Methods and results: Forty-two RCTs were eligible for this meta-analysis after searching the PubMed, Cochrane, and Embase databases. Pooled estimates demonstrated that treatment with microbial therapy significantly reduced the waist circumference (WC) (SMD = −0.26, 95% CI −0.49, −0.03), fasting blood glucose (FBG) (SMD = −0.35, 95% CI −0.52, −0.18), total cholesterol (TC) (SMD = −0.36, 95% CI −0.55, −0.17), low-density lipoprotein cholesterol (LDL-C) (SMD = −0.42, 95% CI −0.61, −0.22), and triacylglycerol (TG)(SMD = −0.38, 95% CI −0.55, −0.20), but increased the high-density lipoprotein cholesterol (HDL-C) (SMD = 0.28, 95% CI.03, 0.52). Sensitivity analysis indicated that after eliminating one study utilizing Bifidobacteriumlactis, results became statistically significant in diastolic blood pressure (DBP) (SMD = −0.24, 95% CI −0.41, −0.07) and in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (SMD = −0.28, 95% CI −0.54, −0.03), while the body mass index (BMI) showed significant difference after eliminating one study utilizing oat bran (SMD = −0.16, 95% CI −0.31, −0.01). There was still no significant effect in systolic blood pressure (SBP) and in hemoglobin A1c (HbA1c%).

Conclusion: In patients with MetS, the conditioning with microbial therapy notably improves FBG, TC, TG, HDL-C, LDL-C, WC, BMI (except for the study using oat bran), HOMA-IR, and DBP (except for the Study using Bifidobacteriumlactis), however, with no effect in SBP and in HbA1c%.
Sunflower (Helianthus annuus L.) Seed Hull Waste: Composition, Antioxidant Activity, and Filler Performance in Pectin-Based Film Composites
Authors: De'Nobili Maria D. , Bernhardt Dana C. , Basanta Maria F. , Rojas Ana M.
Published: December 2021

Helianthus annuus L. seed hull is an abundant waste of the edible oil industry. To envisage potential applications of this waste, here, we aimed to analyze the chemical composition of milled sunflower hulls (SP), constituted mainly by 210 μm (51.4%) and 420 μm (27.6%) average mesh particle sizes. SP contained almost 30% of cellulose, 26.4% of lignin, 38.5% of neutral sugars, mainly hemicelluloses, and only 1.3% of proteins. The important lignin content and low pectin content (4.0% of uronic acids) present in SP were both ascribed to its low hydrophilic behavior and hydration capacity. Phenolic compounds were mostly proanthocyanidins (168 mg/100 g SP), with lower amounts of extractable (31.4 mg/100 g SP) phenolics (O-caffeoylquinic acid), all of them associated with the DPPH radical scavenging capacity (95 mg ascorbic acid equiv./100 g) and ferric reducing power (FRAP: 152 mg ascorbic acid equiv./100 g) shown by SP. Esterified ferulic acid (52.9 mg/100 g SP) was also found, mostly as monomers and trimers. SP of 53 μm particle size was then assayed as a filler (0, 5, 8, and 12% concentrations) in calcium low methoxyl pectin-based films, which showed antioxidant capacity (DPPH and FRAP assays) in an SP-concentration-dependent manner. SP showed homogeneous dispersion in composite films equilibrated at 57.7% relative humidity. Water content decreased while film thickness increased with SP concentration. When loaded at a 12% level, the presence of 53-μm SP decreased the water vapor permeability and increased the normal stress at film fracture. Sunflower hulls can then be applied to the development of active materials like 12% SP film, which can be proposed as a food slice antioxidant separator to be investigated in a future work.
Configuration of the Volatile Aromatic Profile of Carob Powder Milled From Pods of Genetic Variants Harvested at Progressive Stages of Ripening From High and Low Altitudes
Authors: Antoniou Chrystalla , Kyratzis Angelos C. , Soteriou Georgios A. , Rouphael Youssef , Kyriacou Marios C.
Published: December 2021

Carob powder is increasingly valued as a substitute for cocoa and as a flavor-enhancing component of processed foods. However, little is known about the impact of preharvest factors such as fruit maturity, genotype and altitude on its volatile organic compounds (VOCs) composition. The current study examined the VOCs composition of powder milled from pods of two genotypes cultivated at 15 and 510 m altitude and harvested at six progressive stages of maturity, ranging from fully developed immature green (RS1) to late ripe (RS6). Fifty-six VOCs categorized into acids, esters, aldehydes, ketones, alcohols, furans, and alkanes were identified through HS-SPME GC-MS analysis. Maturity was the most influential factor, followed by altitude and least by genotype. Aldehydes and alcohols correlated positively (r= 0.789;p< 0.001), both accumulated in immature carobs and decreased with progressive ripening, resulting in the attenuation of green grassy aroma. Conversely, acids increased with ripening and dominated the carob volatilome at full maturity, correlating negatively with aldehydes and alcohols (r= −0.835 andr= −0.950, respectively;p< 0.001). The most abundant VOC throughout ripening (17.3-57.7%) was isobutyric acid, responsible for the characteristic cheesy-acidic-buttery aroma of carob powder. The pleasurable aroma detected at the immature stages (RS2 and RS3) was traced to isobutyrate and methyl isobutyrate esters, rendering unripe green carob powder a potential admixture component for improving the aroma of novel food products. Lower altitude favored the accumulation of acids linked to less pleasant aroma, whereas isobutyric acid was more abundant at higher altitude. This constitutes a significant indication that higher altitude enhances the characteristic carob-like aroma and sensory quality of carob powder.
Sirt1 Promotes the Restoration of Hepatic Progenitor Cell (HPC)-Mediated Liver Fatty Injury in NAFLD Through Activating the Wnt/β-Catenin Signal Pathway
Authors: Li Qinjin , Gong Yuqing , Wang Yi , Liu Bingbing , Chu Yi , Gui Sisi , Zheng Yazhen , Chen Xiaodong
Published: December 2021

Non-alcoholic fatty liver disease (NAFLD) has developed into the world's largest chronic epidemic. In NAFLD, hepatic steatosis causes hepatocytes dysfunction and even apoptosis. The liver has a strong restoration or regeneration ability after an injury, however, it is unclear through which pattern fatty liver injury in NAFLD is repaired and what the repair mechanism is. Here, we found that in the high-fat diet (HFD)-induced NAFLD mice model, fatty liver injury caused the significant ductular reaction (DR), which is a marker to promote the repair of liver injury. SOX9+ and HNF4α+ biphenotype also suggested that hepatic progenitor cells (HPCs) were activated by fatty liver injury in the HFD-elicited NAFLD mice model. Concurrently, fatty liver injury also activated the Wnt/β-catenin signal pathway, which is a necessary process for HPC differentiation into mature hepatocytes. However, Sirt1 knockdown weakened HPC activation and Wnt/β-catenin signal in Sirt1+/− mice with HFD feeding. In rat-derived WB-F344 hepatic stem cell line, Sirt1 overexpression (OE) or Sirt1 activator–Resveratrol promoted HPC differentiation via activating Wnt/β-catenin signal pathway. Glycogen PAS staining demonstrated that Sirt1 OE promoted WB-F344 cells to differentiate into mature hepatocytes with glycogen synthesis ability, while Sirt1 inhibitor EX527 or Wnt/β-catenin pathway inhibitor HF535 decreased glycogen positive cells. Together, our data suggested that Sirt1 plays a vital role in activating HPCs to repair fatty liver injury or promote liver regeneration through the Wnt/β-catenin signal pathway in NAFLD, which might provide a new strategy for fatty liver injury or NAFLD therapy.
YBX1 Enhances Metastasis and Stemness by Transcriptionally Regulating MUC1 in Lung Adenocarcinoma
Authors: Xie Qiang , Zhao Shilei , Liu Wenzhi , Cui Yanwei , Li Fengzhou , Li Zhuoshi , Guo Tao , Yu Wendan , Guo Wei , Deng Wuguo , Gu Chundong
Published: December 2021

Abnormal expression of the transcription factor Y-box-binding protein-1 (YBX1) is associated with the proliferation, migration, aggressiveness, and stem-like properties of various cancers. These characteristics contribute to the tumorigenesis and metastasis of cancer. We found that the expression levels of Mucin-1 (MUC1) and YBX1 were positively correlated in lung adenocarcinoma cells and lung adenocarcinoma tissue. Our retrospective cohort study of 176 lung adenocarcinoma patients after surgery showed that low expression of both YBX1 and MUC1 was an independent predictor of the prognosis and recurrence of lung adenocarcinoma. In lung adenocarcinoma cells, the silencing/overexpression of YBX1 caused a simultaneous change in MUC1, and MUC1 overexpression partially reversed the decreased tumor cell migration, aggressiveness, and stemness caused by YBX1 silencing. Moreover, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays proved that MUC1 was the downstream target of YBX1 and that YBX1 bound to the -1480~-1476 position in the promoter region of MUC1 to regulate its transcription. Furthermore, in mouse xenograft models and a lung cancer metastasis model, MUC1, which is downstream of YBX1, partially reversed the decreased number and size of tumors caused by YBX1 silencing. In conclusion, our findings indicated a novel mechanism by which YBX1 promotes the stemness and metastasis of lung adenocarcinoma by targeting MUC1 and provided a combination approach for diagnosis different from traditional single tumor biomarkers to predict patient prognosis and provide clinical treatment targets.
Systematic Analysis of an Invasion-Related 3-Gene Signature and Its Validation as a Prognostic Model for Pancreatic Cancer
Authors: Xu Dafeng , Wang Yu , Zhang Yuliang , Liu Zhehao , Chen Yonghai , Zheng Jinfang
Published: December 2021

Background

Pancreatic adenocarcinoma (PAAD) is a malignant tumor of the digestive system that is associated with a poor prognosis in patients owing to its rapid progression and high invasiveness.

Methods

Ninety-seven invasive-related genes obtained from the CancerSEA database were clustered to obtain the molecular subtype of pancreatic cancer based on the RNA-sequencing (RNA-seq) data of The Cancer Genome Atlas (TCGA). The differentially expressed genes (DEGs) between subtypes were obtained using the limma package in R, and the multi-gene risk model based on DEGs was constructed by Lasso regression analysis. Independent datasets GSE57495 and GSE62452 were used to validate the prognostic value of the risk model. To further explore the expression of the hub genes, immunohistochemistry was performed on PAAD tissues obtained from a large cohort.

Results

The TCGA-PAAD samples were divided into two subtypes based on the expression of the invasion-related genes: C1 and C2. Most genes were overexpressed in the C1 subtype. The C1 subtype was mainly enriched in tumor-related signaling pathways, and the prognosis of patients with the C1 subtype was significantly worse than those with the C2 subtype. A 3-gene signature consisting of LY6D, BCAT1, and ITGB6 based on 538 DEGs between both subtypes serves as a stable prognostic marker in patients with pancreatic cancer across multiple cohorts. LY6D, BCAT1, and ITGB6 were over-expressed in 120 PAAD samples compared to normal samples.

Conclusions

The constructed 3-gene signature can be used as a molecular marker to assess the prognostic risk in patients with PAAD.
EGFR-Dependent Extracellular Matrix Protein Interactions Might Light a Candle in Cell Behavior of Non-Small Cell Lung Cancer
Authors: Hassanein Sarah Sayed , Abdel-Mawgood Ahmed Lotfy , Ibrahim Sherif Abdelaziz
Published: December 2021

Lung cancer remains the leading cause of cancer-related death and is associated with a poor prognosis. Lung cancer is divided into 2 main types: the major in incidence is non-small cell lung cancer (NSCLC) and the minor is small cell lung cancer (SCLC). Although NSCLC progression depends on driver mutations, it is also affected by the extracellular matrix (ECM) interactions that activate their corresponding signaling molecules in concert with integrins and matrix metalloproteinases (MMPs). These signaling molecules include cytoplasmic kinases, small GTPases, adapter proteins, and receptor tyrosine kinases (RTKs), particularly the epidermal growth factor receptor (EGFR). In NSCLC, the interplay between ECM and EGFR regulates ECM stiffness, angiogenesis, survival, adhesion, migration, and metastasis. Furthermore, some tumor-promoting ECM components (e.g., glycoproteins and proteoglycans) enhance activation of EGFR and loss of PTEN. On the other hand, other tumor-suppressing glycoproteins and -proteoglycans can inhibit EGFR activation, suppressing cell invasion and migration. Therefore, deciphering the molecular mechanisms underlying EGFR and ECM interactions might provide a better understanding of disease pathobiology and aid in developing therapeutic strategies. This review critically discusses the crosstalk between EGFR and ECM affecting cell behavior of NSCLC, as well as the involvement of ECM components in developing resistance to EGFR inhibition.
UDCA Inhibits Hypoxic Hepatocellular Carcinoma Cell–Induced Angiogenesis Through Suppressing HIF-1α/VEGF/IL-8 Intercellular Signaling
Authors: Lin Wanfu , Li Shu , Meng Yongbin , Huang Guokai , Liang Shufang , Du Juan , Liu Qun , Cheng Binbin
Published: December 2021

Background: A hypoxic microenvironment may induce angiogenesis and promote the development of hepatocellular carcinoma (HCC). The aim of this study was to evaluate whether ursodeoxycholic acid (UDCA) may inhibit hypoxic HCC cell–induced angiogenesis and the possible mechanisms.

Methods: Tube formation and matrigel plug angiogenesis assays were used to evaluate angiogenesis in vitro and in vivo, respectively. Real-time PCR, enzyme-linked immunosorbent assay, and Western blot were used to evaluate the mRNA and protein expressions of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and IL-8, respectively. Dual-luciferase reporter assay was applied to assess the reporter gene expression of hypoxia-response element (HRE).

Results: UDCA antagonized hypoxic Huh 7 cell-induced tube formation of EA.hy 926 cells. In HCC cells, UDCA inhibited hypoxia-induced upregulation of VEGF and IL-8 both in mRNA and protein levels. UDCA also inhibited IL-8–induced angiogenesis in vitro and in vivo through suppressing IL-8–induced phosphorylation of ERK. The levels of HIF-1α mRNA and protein and HRE-driven luciferase activity in HCC cells were upregulated by hypoxia and were all inhibited by UDCA. The proteasome inhibitor MG132 antagonized the effect of UDCA on HIF-1α degradation. In hypoxic condition, the phosphorylation of ERK and AKT was obviously increased in HCC cells, which was suppressed by UDCA. Transfection of the HIF-1α overexpression plasmid reversed the effects of UDCA on hypoxic HCC cell–induced angiogenesis, HRE activity, and expressions of IL-8 and VEGF.

Conclusions: Our results demonstrated that UDCA could inhibit hypoxic HCC cell–induced angiogenesis through suppressing HIF-1α/VEGF/IL-8–mediated intercellular signaling between HCC cells and endothelial cells.
Rheum tanguticum Alleviates Cognitive Impairment in APP/PS1 Mice by Regulating Drug-Responsive Bacteria and Their Corresponding Microbial Metabolites
Authors: Gao Demin , Zhao Huizhen , Yin Zhihui , Han Chen , Wang Ying , Luo Gan , Gao Xiaoyan
Published: December 2021

Drugs targeting intestinal bacteria have shown great efficacy for alleviating symptoms of Alzheimer’s disease (AD), and microbial metabolites are important messengers. Our previous work indicated that Rheum tanguticum effectively improved cognitive function and reshaped the gut microbial homeostasis in AD rats. However, its therapeutic mechanisms remain unclear. Herein, this study aimed to elaborate the mechanisms of rhubarb for the treatment of AD by identifying effective metabolites associated with rhubarb-responsive bacteria. The results found that rhubarb reduced hippocampal inflammation and neuronal damage in APP/PS1 transgenic (Tg) mice. 16S rRNA sequencing and metabolomic analysis revealed that gut microbiota and their metabolism in Tg mice were disturbed in an age-dependent manner. Rhubarb-responsive bacteria were further identified by real-time polymerase chain reaction (RT-PCR) sequencing. Four different metabolites reversed by rhubarb were found in the position of the important nodes on rhubarb-responsive bacteria and their corresponding metabolites combined with pathological indicators co-network. Furthermore, in vitro experiments demonstrated o-tyrosine not only inhibited the viabilities of primary neurons as well as BV-2 cells, but also increased the levels of intracellular reactive oxygen species and nitric oxide. In the end, the results suggest that rhubarb ameliorates cognitive impairment in Tg mice through decreasing the abundance of o-tyrosine in the gut owing to the regulation of rhubarb-responsive bacteria. Our study provides a promising strategy for elaborating therapeutic mechanisms of bacteria-targeted drugs for AD.
Puerarin Alleviates Depression-Like Behavior Induced by High-Fat Diet Combined With Chronic Unpredictable Mild Stress via Repairing TLR4-Induced Inflammatory Damages and Phospholipid Metabolism Disorders
Authors: Gao Li-Na , Yan Maocai , Zhou Lirun , Wang Jian’an , Sai Chunmei , Fu Yingjie , Liu Yang , Ding Lin
Published: December 2021

Puerarin has been reported as a potential agent for neuro-inflammatory disorders. However, there have been no reports of using puerarin for the treatment of depression based on Toll-like receptor 4 (TLR4)–mediated inflammatory injury. In this study, we evaluated the protective effects of puerarin on depression-like rats induced by a high-fat diet (HFD) combined with chronic unpredictable mild stress (CUMS). The mechanism was screened by lipidomics and molecular docking and confirmed by in vivo tests. Puerarin treatment significantly improved 1% sucrose preference and ameliorated depression-like behavior in the open-field test. The antidepressive effects of puerarin were associated with decreased pro-inflammatory cytokine production, including interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and increased anti-inflammatory cytokine levels (IL-10) in rat hippocampal tissues and plasma. Hematoxylin–eosin (H&E), immunofluorescence staining, and Western blotting results displayed that puerarin alleviated inflammatory injury by suppressing TLR4 expression and by repairing the intestine mucus barrier via enhancing the expression of claudin-1 and occludin. Non-targeted lipidomics analysis showed that the most significantly different metabolites modified by puerarin were phospholipids. Puerarin treatment–altered biomarkers were identified as PC (15:1/20:1), PE (15:1/16:1), and PI (18:2/20:1) in comparison with the HFD/CUMS group. Molecular docking modeling revealed that puerarin could bind with cytosolic phospholipase A2 (cPLA2) and cyclooxygenase-2 (COX-2), which play central roles in TLR4-mediated phospholipid metabolism. In vivo, puerarin treatment decreased the enzyme activities of cPLA2 and COX-2, resulting in lower production of prostaglandin E2 (PGE2) in hippocampal and intestinal tissues. In conclusion, puerarin treatment reverses HFD/CUMS-induced depression-like behavior by inhibiting TLR4-mediated intestine mucus barrier dysfunction and neuro-inflammatory damages via the TLR4/cPLA2/COX-2 pathway.
Mechanism of Hedyotis Diffusa in the Treatment of Cervical Cancer
Authors: Qian Kai , Fu Dan , Jiang Baorui , Wang Yue , Tian Fei , Song Li , Li Lei
Published: December 2021

Cervical cancer is one of the most common malignant tumors among women in the world. In clinical practice, Hedyotis diffusa has pharmacological effects in treating cervical cancer, but its components are relatively complex, and the mechanism of Hedyotis diffusa in treating cervical cancer is still unclear. In this work, the potential active components and mechanism of Hedyotis diffusa in the treatment of cervical cancer were explored by means of network pharmacology. By constructing its active ingredient-target network, and enriching and analyzing the targets, we found the key targets and their effective components (beta-Sitosterol and Quercetin) that play a therapeutic role. Finally, we evaluated the prognostic value of the core target genes through survival analysis. Our work initially explored the therapeutic mechanism of cervical cancer, which lays a theoretical foundation for further exploring its pharmacological action and its clinical application.
Frequent Manipulation of Resistance Training Variables Promotes Myofibrillar Spacing Changes in Resistance-Trained Individuals
Authors: Fox Carlton D. , Mesquita Paulo H. C. , Godwin Joshua S. , Angleri Vitor , Damas Felipe , Ruple Bradley A. , Sexton Casey L. , Brown Michael D. , Kavazis Andreas N. , Young Kaelin C. , Ugrinowitsch Carlos , Libardi Cleiton A. , Roberts Michael D.
Published: December 2021

We sought to determine if manipulating resistance training (RT) variables differentially altered the expression of select sarcoplasmic and myofibril proteins as well as myofibrillar spacing in myofibers. Resistance-trained men (n = 20; 26 ± 3 years old) trained for 8 weeks where a randomized leg performed either a standard (CON) or variable RT protocol (VAR: manipulation of load, volume, muscle action, and rest intervals at each RT session). A pre-training (PRE) vastus lateralis biopsy was obtained from a randomized single leg, and biopsies were obtained from both legs 96 h following the last training bout. The sarcoplasmic protein pool was assayed for proteins involved in energy metabolism, and the myofibril protein pool was assayed for relative myosin heavy chain (MHC) and actin protein abundances. Sections were also histologically analyzed to obtain myofibril spacing characteristics. VAR resulted in ~12% greater volume load (VL) compared to CON (p < 0.001). The mean fiber cross-sectional area increased following both RT protocols [CON: 14.6% (775.5 μm2), p = 0.006; VAR: 13.9% (743.2 μm2), p = 0.01 vs. PRE for both], but without significant differences between protocols (p = 0.79). Neither RT protocol affected a majority of assayed proteins related to energy metabolism, but both training protocols increased hexokinase 2 protein levels and decreased a mitochondrial beta-oxidation marker (VLCAD protein; p < 0.05). Citrate synthase activity levels increased with CON RT (p < 0.05), but not VAR RT. The relative abundance of MHC (summed isoforms) decreased with both training protocols (p < 0.05). However, the relative abundance of actin protein (summed isoforms) decreased with VAR only (13.5 and 9.0%, respectively; p < 0.05). A decrease in percent area occupied by myofibrils was observed from PRE to VAR (−4.87%; p = 0.048), but not for the CON (4.53%; p = 0.979). In contrast, there was an increase in percent area occupied by non-contractile space from PRE to VAR (10.14%; p = 0.048), but not PRE to CON (0.72%; p = 0.979). In conclusion, while both RT protocols increased muscle fiber hypertrophy, a higher volume-load where RT variables were frequently manipulated increased non-contractile spacing in resistance-trained individuals.
Fatigue Monitoring Through Wearables: A State-of-the-Art Review
Authors: Adão Martins Neusa R. , Annaheim Simon , Spengler Christina M. , Rossi René M.
Published: December 2021

The objective measurement of fatigue is of critical relevance in areas such as occupational health and safety as fatigue impairs cognitive and motor performance, thus reducing productivity and increasing the risk of injury. Wearable systems represent highly promising solutions for fatigue monitoring as they enable continuous, long-term monitoring of biomedical signals in unattended settings, with the required comfort and non-intrusiveness. This is a p rerequisite for the development of accurate models for fatigue monitoring in real-time. However, monitoring fatigue through wearable devices imposes unique challenges. To provide an overview of the current state-of-the-art in monitoring variables associated with fatigue via wearables and to detect potential gaps and pitfalls in current knowledge, a systematic review was performed. The Scopus and PubMed databases were searched for articles published in English since 2015, having the terms “fatigue,” “drowsiness,” “vigilance,” or “alertness” in the title, and proposing wearable device-based systems for non-invasive fatigue quantification. Of the 612 retrieved articles, 60 satisfied the inclusion criteria. Included studies were mainly of short duration and conducted in laboratory settings. In general, researchers developed fatigue models based on motion (MOT), electroencephalogram (EEG), photoplethysmogram (PPG), electrocardiogram (ECG), galvanic skin response (GSR), electromyogram (EMG), skin temperature (Tsk), eye movement (EYE), and respiratory (RES) data acquired by wearable devices available in the market. Supervised machine learning models, and more specifically, binary classification models, are predominant among the proposed fatigue quantification approaches. These models were considered to perform very well in detecting fatigue, however, little effort was made to ensure the use of high-quality data during model development. Together, the findings of this review reveal that methodological limitations have hindered the generalizability and real-world applicability of most of the proposed fatigue models. Considerably more work is needed to fully explore the potential of wearables for fatigue quantification as well as to better understand the relationship between fatigue and changes in physiological variables.