bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of brain microstructure alterations on diffusion kurtosis imaging among Alzheimer’s disease, mild cognitive impairment, and cognitively normal individuals
Authors: Chu Xiaoqi , Wu Peng , Yan Hongting , Chen Xuejing , Fan Liting , Wu Zheng , Tao Chunmei , Ma Yue , Fu Yu , Guo Yunchu , Dong Yang , Yang Chao , Ge Yusong
Published: August 2022

Objective

Our study aimed to explore the differences in brain microstructure in patients with Alzheimer’s disease (AD) and with mild cognitive impairment (MCI) and in individuals with normal cognition using diffusion kurtosis imaging (DKI) to identify a potential non-invasive biomarker of AD.

Materials and methods

A total of 61 subjects were included in our study, including 20 subjects diagnosed with AD, 21 patients diagnosed with amnestic MCI, and 20 cognitively normal individuals. We acquired magnetic resonance imaging (MRI) scans, and DKI images were processed. Twelve regions of interest were drawn, and various parameters were measured and analyzed using SPSS version 11.0 software.

Results

Comparative analysis showed that differences in brain regions in terms of mean diffusion (MD) and mean kurtosis (MK) between groups were the most marked. Precuneus MD, temporal MK, precuneus MK, and hippocampal MK were significantly correlated with neuropsychological test scores. Hippocampal MK showed the strongest correlation with the medial temporal lobe atrophy score (r = −0.510), and precuneus MD had the strongest correlation with the Koedam score (r = 0.463). The receiver operating curve analysis revealed that hippocampal MK exhibited better diagnostic efficacy than precuneus MD for comparisons between any group pair.

Conclusion

DKI is capable of detecting differences in brain microstructure between patients with AD, patients with MCI, and cognitively normal individuals. Moreover, it compensates for the deficiencies of conventional MRI in detecting pathological changes in microstructure before the appearance of macroscopic atrophy. Hippocampus MK was the most sensitive single parameter map for differentiating patients with AD, patients with MCI, and cognitively normal individuals.
Effects of exercise intervention on executive function of middle-aged and elderly people: A systematic review of randomized controlled trials
Authors: Zheng Jian , Su Xuan , Xu Chang
Published: August 2022

Background

Executive function will gradually decline with the increase of age, which will have a negative impact on the quality of life and general health. Exercise intervention can improve executive function and prevent its deterioration, but the evidence from randomized controlled trials is not consistent.

Aim

To assess the effect of exercise intervention on executive function of healthy middle-aged and elderly people, and briefly describe its mechanism.

Methods

A search was conducted using PubMed, Web of science and EBSCO. The searches were limited to English articles published from January 2010 to January 2022. The information is extracted from searched articles included or excluded based on certain criteria.

Results

The search returned 2,746 records, of which 11 articles were included in the systematic review, and 8 articles were supplemented according to the references included and related reviews. The results show that different types of exercise intervention have positive effects on the executive function of the middle-aged and elderly people. The intervention prescriptions in most studies are executed in medium to low frequency, medium intensity and medium duration, while only 11% of the studies were followed up.

Conclusions

The intervention, which was executed twice a week with 30–60 min single intervention time and over 12 weeks total duration, showed a good intervention effect. Exercise intervention is to improve executive function by affecting the activation of brain network and the synthesis of neurotransmitters.
The forgotten tonsils—does the immune active organ absorb nanoplastics?
Authors: Ekvall Mikael T. , Naidu Shanti , Lundqvist Martin , Cedervall Tommy , Värendh Maria
Published: August 2022

Nanoplastics are defined as plastic particles broken down to extremely small sizes (1–100 nm) with unknown effects to the human body and immune system. Air and food exposure scenarios involving blood, lungs and intestine are considered in the literature. The fact that plastics also needs to pass the nose, oral cavity, and throat is so far ignored in the literature. The tonsils are immunologically important tissue in the oral cavity in which ingested and inhaled agents are incorporated through crypts with the capacity to capture agents and start early immunologic reactions. We argue that the tonsil is a very important tissue to study in regard to micro and nanoplastic human exposure and immunologic response. Nano-sized particles are known to be able to travel through the natural barriers and have different effects on biology compared to larger particle and the bulk material. It is therefore, although difficult, important to develop experimental methods to detect and identify nanoplastics in the tonsils. In preliminary experiments we have optimized the breakdown of tonsil tissues and tried to retrieve added polystyrene nanoparticles using density-based separation and concentration. The polystyrene was followed by FTIR spectrometry and could be detected in micro- and nano-size, in the tissue breakdown solution but not after density-based separation. When nanoplastics are incorporated in the human body, it is possible that the small plastic pieces can be detected in the tonsil tissue, in the lymph system and it is of importance for future studies to reveal the immunological effects for humans.
Chronic corticosterone administration in adolescence enhances dorsolateral striatum-dependent learning in adulthood
Authors: Gadberry Ty M. , Goodman Jarid , Packard Mark G.
Published: August 2022

Previous evidence indicates a link between early life stress (ELS) in humans and a predisposition to psychopathologies that are characterized in part by maladaptive habitual behaviors. Stress and anxiety influence the relative use of mammalian memory systems implicated in these disorders. Specifically, cognitive memory functions of the hippocampus are typically impaired by stress/anxiety, whereas habit memory functions of the dorsolateral striatum (DLS) are enhanced. A stress/anxiety bias toward habit memory has largely been demonstrated in adult rodents and humans, and the effects of ELS on the later use of DLS-dependent habit memory in adult rodents have not been extensively examined. The present study addressed this question by chronically elevating corticosterone (CORT) during adolescence, and investigated the effects of this treatment on DLS-dependent habit learning in adulthood. In experiment 1, adolescent rats received a single daily injection of either CORT (5 mg/kg) or vehicle (cVEH) over 5 days and then matured undisturbed before training as adults in a DLS-dependent water plus-maze task. Rats administered CORT injections during adolescence displayed a strong trend toward enhanced learning during adulthood relative to vehicle-treated rats. Adolescent CORT administration also increased anxiety-like behavior in adulthood in an elevated plus-maze. In experiment 2, adolescent CORT administration enhanced task acquisition in adulthood, and this effect was blocked by concurrent administration of the glucocorticoid antagonist mifepristone (30 mg/kg). Taken together, these findings suggest that chronic elevation of glucocorticoids during adolescence are sufficient to facilitate habit learning in adulthood, and indicate that glucocorticoid function may be a potential underlying mechanism by which ELS influences subsequent habitual behaviors.
Object recognition tasks in rats: Does sex matter?
Authors: Becegato Marcela , Silva Regina H.
Published: August 2022

Novelty recognition tasks based on object exploration are frequently used for the evaluation of cognitive abilities and investigation of neurobiological and molecular aspects of memory in rodents. This is an interesting approach because variations of the object recognition tasks focus on different aspects of the memory events such as novelty, location, context, and combinations of these elements. Nevertheless, as in most animal neuroscience research, female subjects are underrepresented in object recognition studies. When studies include females, the particularities of this sex are not always considered. For example, appropriate controls for manipulations conducted exclusively in females (such as estrous cycle verification) are not included. In addition, interpretation of data is often based on standardizations conducted with male subjects. Despite that, females are frequently reported as deficient and unable to adequately perform some memory tests. Thus, our study aims to review studies that describe similarities and differences between male and female performances in the different variations of object recognition tasks. In summary, although females are commonly described with deficits and the articles emphasize sex differences, most published data reveal similar performances when sexes are compared.
All roads lead to heterogeneity: The complex involvement of astrocytes and microglia in the pathogenesis of Alzheimer’s disease
Authors: St-Pierre Marie-Kim , VanderZwaag Jared , Loewen Sophia , Tremblay Marie-Ève
Published: August 2022

In recent years, glial cells have been acknowledged as key players in the pathogenesis of Alzheimer’s disease (AD), a neurodegenerative condition in which an accumulation of intracellular neurofibrillary tangles and extracellular fibrillar amyloid beta is notably observed in the central nervous system. Genome-wide association studies have shown, both in microglia and astrocytes, an increase in gene variants associated with a higher risk of developing late-onset AD. Microglia, the resident innate immune cells of the brain, and astrocytes, glial cells crucial for vascular integrity and neuronal support, both agglomerate near amyloid beta plaques and dystrophic neurites where they participate in the elimination of these harmful parenchymal elements. However, their role in AD pathogenesis has been challenging to resolve due to the highly heterogeneous nature of these cell populations, i.e., their molecular, morphological, and ultrastructural diversity, together with their ever-changing responsiveness and functions throughout the pathological course of AD. With the recent expansions in the field of glial heterogeneity through innovative advances in state-of-the-art microscopy and -omics techniques, novel concepts and questions arose, notably pertaining to how the diverse microglial and astrocytic states interact with each other and with the AD hallmarks, and how their concerted efforts/actions impact the progression of the disease. In this review, we discuss the recent advances and findings on the topic of glial heterogeneity, particularly focusing on the relationships of these cells with AD hallmarks (e.g., amyloid beta plaques, neurofibrillary tangles, synaptic loss, and dystrophic neurites) in murine models of AD pathology and post-mortem brain samples of patients with AD.
E2ENNet: An end-to-end neural network for emotional brain-computer interface
Authors: Han Zhichao , Chang Hongli , Zhou Xiaoyan , Wang Jihao , Wang Lili , Shao Yongbin
Published: August 2022

Objectve

Emotional brain-computer interface can recognize or regulate human emotions for workload detection and auxiliary diagnosis of mental illness. However, the existing EEG emotion recognition is carried out step by step in feature engineering and classification, resulting in high engineering complexity and limiting practical applications in traditional EEG emotion recognition tasks. We propose an end-to-end neural network, i.e., E2ENNet.

Methods

Baseline removal and sliding window slice used for preprocessing of the raw EEG signal, convolution blocks extracted features, LSTM network obtained the correlations of features, and the softmax function classified emotions.

Results

Extensive experiments in subject-dependent experimental protocol are conducted to evaluate the performance of the proposed E2ENNet, achieves state-of-the-art accuracy on three public datasets, i.e., 96.28% of 2-category experiment on DEAP dataset, 98.1% of 2-category experiment on DREAMER dataset, and 41.73% of 7-category experiment on MPED dataset.

Conclusion

Experimental results show that E2ENNet can directly extract more discriminative features from raw EEG signals.

Significance

This study provides a methodology for implementing a plug-and-play emotional brain-computer interface system.
Neuronal ceroid lipofuscinosis in the South American-Caribbean region: An epidemiological overview
Authors: Guelbert Guillermo , Venier Ana Clara , Cismondi Ines Adriana , Becerra Adriana , Vazquez Juan Carlos , Fernández Elmer Andrés , De Paul Ana Lucía , Guelbert Norberto , Noher Ines , Pesaola Favio
Published: August 2022

Neuronal ceroid lipofuscinoses (NCLs) comprise 13 hereditary neurodegenerative pathologies of very low frequency that affect individuals of all ages around the world. All NCLs share a set of symptoms that are similar to other diseases. The exhaustive collection of data from diverse sources (clinical, genetic, neurology, ophthalmology, etc.) would allow being able in the future to define this group with greater precision for a more efficient diagnostic and therapeutic approach. Despite the large amount of information worldwide, a detailed study of the characteristics of the NCLs in South America and the Caribbean region (SA&C) has not yet been done. Here, we aim to present and analyse the multidisciplinary evidence from all the SA&C with qualitative weighting and biostatistical evaluation of the casuistry. Seventy-one publications from seven countries were reviewed, and data from 261 individuals (including 44 individuals from the Cordoba cohort) were collected. Each NCL disease, as well as phenotypical and genetic data were described and discussed in the whole group. The CLN2, CLN6, and CLN3 disorders are the most frequent in the region. Eighty-seven percent of the individuals were 10 years old or less at the onset of symptoms. Seizures were the most common symptom, both at onset (51%) and throughout the disease course, followed by language (16%), motor (15%), and visual impairments (11%). Although symptoms were similar in all NCLs, some chronological differences could be observed. Sixty DNA variants were described, ranging from single nucleotide variants to large chromosomal deletions. The diagnostic odyssey was probably substantially decreased after medical education activities promoted by the pharmaceutical industry and parent organizations in some SA&C countries. There is a statistical deviation in the data probably due to the approval of the enzyme replacement therapy for CLN2 disease, which has led to a greater interest among the medical community for the early description of this pathology. As a general conclusion, it became clear in this work that the combined bibliographical/retrospective evaluation approach allowed a general overview of the multidisciplinary components and the epidemiological tendencies of NCLs in the SA&C region.
An integrated intervention of computerized cognitive training and physical exercise in virtual reality for people with Alzheimer's disease: The jDome study protocol
Authors: Gambella Elena , Margaritini Arianna , Benadduci Marco , Rossi Lorena , D'Ascoli Paola , Riccardi Giovanni R. , Pasquini Sara , Civerchia Patrizia , Pelliccioni Giuseppe , Bevilacqua Roberta , Maranesi Elvira
Published: August 2022

Introduction

Alzheimer's disease is a neurodegenerative syndrome characterized by cognitive deficits, loss of daily functions, and mental and behavioral disorders, which cause stress and negatively affect the quality of life. Studies in the field suggest that combining cognitive training with physical activity can reduce the risk of developing the disease and, once neurodegeneration has begun, it slows its progress. In particular, virtual reality and augmented reality administer cognitive stimulation while providing a link to autobiographical memory through reminiscence, enabling the improvement of the person's quality of life. The present protocol aims to evaluate the effectiveness of cognitive and physical treatments, integrated with the addition of virtual reality and reminiscence elements, using the Brainer software, in which people will find cognitive training, and the jDome® BikeAround™ system, which will allow participants to pedal along a personalized path projected on a schematic, using an exercise bike connected to the system.

Methods and analysis

For this study, 78 patients with mild Alzheimer's dementia were recruited and divided into the Experimental Group (EG) and Control Group (CG). Sixteen treatment sessions of 60 min each were conducted for both groups (2 training sessions per week, for 8 weeks), including 1 patient at a time. The EG received cognitive treatment with Brainer and physical training with jDome, while the CG received cognitive treatment with Brainer and physical training with a classic bicycle. The evaluation mainly focused on the assessment of the person's cognitive status. Other analyses were conducted on the quality of life, mood, behavioral disorders, and physical function, which were considered secondary outcomes.

Discussions

The ultimate goal of the present study is to test the effectiveness of a treatment for people with mild Alzheimer's focused on the integration of cognitive training and aerobic physical activity, using an exercise bike, with the addition of virtual reality and reminiscence elements.

Ethics and dissemination

The study was approved by the Ethics Committee of the IRCCS INRCA. It was recorded in ClinicalTrials.gov on 2 June 2022 with the number NCT05402423. The study findings will be used for publication in peer-reviewed scientific journals and presentations in scientific meetings.
Bibliometric analysis of research trends of physical activity intervention for autism spectrum disorders
Authors: Wang Shimeng , Chen Dandan , Yoon Inae , Klich Sebastian , Chen Aiguo
Published: August 2022

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social impairment, restricted interests, and repetitive stereotyped behaviors. At present, its pathogenesis has not been fully understood. Various methods are used for clinical treatment and intervention, among which physical activity (PA) intervention also has an obvious effect. This study has used bibliometric methods and visual analysis methods to analyze 885 studies of PA intervention in ASD from 2003 to 2022 in the Web of Science (WoS) database in order to provide theoretical support for the follow-up research on the effect of PA with ASD. The main findings of this study are as follows. First, the literature on PA interventions in ASD research showed a growing trend. The leading institution in this field is the University of Delaware, forming a core group of authors represented by authors such as Sean Healy and Carol Curtin et al. Second, the research focus of this research area mainly includes PA interventions for children and adolescents with ASD. PA can improve symptoms such as stereotyped behaviors and motor function in patients with ASD as well as can reduce childhood obesity rates and improve quality of life. Third, skill, youth, prevalence, and meta-analysis systematic reviews were found. It is the long-term concern and focus of researchers. In conclusion, the current research is only a short-term analysis, and it is not possible to verify the long-term effect; thus, future data analysis should evaluate and explore the long-term effects of PA interventions on ASD including cohort and longitudinal study types focused on the rehabilitation of patients with ASD. Moreover, testing the sustainability of benefits for children with ASD and constructing a multidimensional exercise integrated intervention model are the main directions for future research in this field.
Glycerol monolaurate ameliorates DSS-induced acute colitis by inhibiting infiltration of Th17, neutrophils, macrophages and altering the gut microbiota
Authors: He Ke-Jie , Dong Jia-Hui , Ouyang Xiao-Mei , Huo Ya-Ni , Cheng Xiao-Shen , Lin Ying , Li Yue , Gong Guoyu , Liu Jingjing , Ren Jian-Lin , Guleng Bayasi
Published: August 2022

Background and aims

Inflammatory bowel disease (IBD) places a heavy medical burden on countries and families due to repeated and prolonged attacks, and the incidence and prevalence of IBD are increasing worldwide. Therefore, finding an effective treatment is a matter of great urgency. Glycerol monolaurate (GML), which has a twelve-carbon chain, is a compound naturally found in human breast milk. Some studies have shown that GML has antibacterial and anti-inflammatory effects. However, the specific mechanism of action remains unclear.

Methods

Acute colitis was established in mice using 3% DSS, and glycerol monolaurate (500 mg·kg−1) was administered for two weeks. QPCR and western blotting were performed to examine the inflammatory status. Mice described were subjected to flow cytometry analysis for immune cell activation.

Results

GML treated alleviated macroscopic symptoms such as shortened colons, increased spleen weight, and caused weight loss in mice with DSS-induced colitis. In addition, GML decreased the expression of pro-inflammatory factors (NF-α, IL-1β and IL-1α) and increased the expression of anti-inflammatory factors (IL-10 and TGF-β). GML inhibited the activation of the MAPK and NF-κB signalling pathways, improved tissue damage, and increased the expression of intestinal tight junction proteins. In addition, LPMCs extracted from intestinal tissue via flow cytometry showed that GML treatment led to a decrease of Th17 cells, Neutrophils and Macrophages. 16S rDNA sequencing showed that GML increased the abundance of commensal bacterium such as Akkermansia and Lactobacillus murinus.

Conclusions

We showed that oral administration of GML ameliorated DSS-induced colitis by inhibiting infiltration of Th17 cells, Neutrophils, and Macrophages, protecting the intestinal mucosal barrier and altered the abundance of commensal bacterium. This study provides new insights into the biological function and therapeutic potential of GML in the treatment of IBD.
Erythrocyte osmotic fragility is not linked to vitamin C nutriture in adults with well-controlled type 2 diabetes
Authors: Lundy Ciara , Fessler Samantha N. , Johnston Carol S.
Published: August 2022

Erythrocyte fragility is amplified by oxidative stress and linked to diabetes-specific microvascular disease. Vitamin C supplementation improves glycemic indices in adults with type 2 diabetes (T2D) by improving antioxidant status. This cross-sectional study examined the relationships between vitamin C status and erythrocyte osmotic fragility in adults with or without T2D. Participants provided a fasting blood sample for erythrocyte osmotic fragility testing as a function of hypotonic NaCl concentrations. Additionally, plasma was stabilized with metaphosphoric acid prior to vitamin C analysis using isocratic reverse-phase UV-HPLC separation. Participants were grouped as diagnosed T2D (n = 14; 36% female; 55.5 ± 8.2 y; 31.5 ± 9.0 kg/m2; HbA1c: 7.4 ± 1.9%; plasma vitamin C: 36.0 ± 12.2 μM) or no diabetes (n = 16; 69% female; 38.7 ± 13.5 y; 26.8 ± 6.6 kg/m2; HbA1c: 5.4 ± 0.3%; plasma vitamin C: 34.8 ± 10.9 μM). Participant characteristics differed between groups only for age and hemoglobin A1c (HbA1c; p < 0.05). All hemolysis parameters were in normal ranges for the participants with T2D, and no significant differences in hemolysis parameters were noted between those with or without T2D. However, among participants with T2D, the NaCl concentration eliciting 50% hemolysis was higher for those with low (<7%) vs. high (>7%) HbA1c values (p = 0.037) indicating a slightly higher erythrocyte fragility in the former group. Vitamin C status did not impact any of the hemolysis parameters in adults with or without T2D. Thus, erythrocyte fragility was not elevated in T2D, and vitamin C nutriture was not related to erythrocyte fragility in adults with well-controlled T2D.
Effective dissecting range and prognostic significance of lateral pelvic lymph node dissection for middle-low rectal cancer patients with lateral pelvic lymph node metastasis: Results of a large multicenter lateral node collaborative group in China
Authors: Zhou Sicheng , Tang Jianqiang , Liang Jianwei , Lou Zheng , Fu Wei , Feng Bo , Yang Yingchi , Xiao Yi , Liu Qian
Published: August 2022

Background

Lateral pelvic lymph node (LPN) metastasis causes increased lateral local recurrence and poor prognosis. We aimed to investigate the prognostic significance and effective range of dissection for the LPN dissection (LPND) in rectal cancer patients with LPN metastasis.

Materials and methods

Through this large, multicenter retrospective cohort study, we evaluated the therapeutic effect of LPND. From January 2012 to December 2019, 387 rectal cancer patients with clinical evidence of LPN metastasis who underwent total mesorectal excision with LPND were included in the study. According to pathological findings, they were divided into negative (n = 296) and positive (n = 91) LPN groups. Primary endpoints were 3-year overall survival (OS), recurrence-free survival (RFS), and local recurrence-free survival (LRFS).

Results

The OS, RFS, and LRFS in the positive group were significantly worse than those in the negative group; However, LPN metastases were not independent prognostic risk factors for LRFS (hazard ratio [HR]: 2.42; 95% confidence interval [CI], 0.77–7.64; P=0.132). Among patients with pathological LPN metastases, LPN metastases to the common and external iliac arteries were independent prognostic risk factors both for OS (HR: 4.74; 95% CI, 1.74–12.90; P=0.002) and RFS (HR: 2.70; 95% CI, 1.16–6.29; P=0.021). No significant difference was observed in the 3-year OS (72.3% vs. 70.2%, P=0.775) and RFS rates (60.9% vs. 52.6%, P=0.408) between patients with metastases to the obturator or internal iliac arteries and patients at N2b stage.

Conclusions

LPND may be effective in controlling local recurrence in patients with LPN metastasis but not systemic metastases. Patients with LPN metastasis limited to the internal iliac and obturator regions achieve a long-term survival benefit from LPND, and their prognoses may be comparable to those at the N2b stage. Further metastasis to the external iliac or common iliac region should be considered systemic disease, and LPND should be avoided.

Clinical Trial Registration

ClinicalTrials.gov, identifier NCT04850027.
Fucosylated exosomal miRNAs as promising biomarkers for the diagnosis of early lung adenocarcinoma
Authors: Chen Xiongfeng , Yu Lili , Hao Kun , Yin Xiaoqing , Tu Mingshu , Cai Liqing , Zhang Liangming , Pan Xiaojie , Gao Qi , Huang Yi
Published: August 2022

Background

Considering the absence of apparent symptoms at the early stage, most patients with lung adenocarcinoma (LUAD) present at an advanced stage, leading to a dismal 5-year survival rate of <20%. Thus, finding perspective non-invasive biomarkers for early LUAD is very essential.

Methods

We developed a fucose-captured strategy based on lentil lectin-magnetic beads to isolate fucosylated exosomes from serum. Then, a prospective study was conducted to define the diagnostic value of serum exosomal miRNAs for early LUAD. A total of 310 participants were enrolled, including 146 LUAD, 98 benign pulmonary nodules (BPNs), and 66 healthy controls (HCs). Firstly, exosome miRNAs in the discovery cohort (n = 24) were profiled by small RNA sequencing. Secondly, 12 differentially expressed miRNAs (DEmiRs) were selected for further screening in a screening cohort (n = 64) by qRT-PCR. Finally, four candidate miRNAs were selected for further validation in a validating cohort (n = 222).

Results

This study demonstrated the feasibility of a fucose-captured strategy for the isolation of fucosylated exosomes from serum, evidenced with exosomal characteristics identified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blotting, as well as rapid and convenient operation of <10 min. Furthermore, a miRNA panel for early LUAD composed of miR4732-5p, miR451a, miR486-5p, and miR139-3p was defined with an AUC of 0.8554 at 91.07% sensitivity and 66.36% specificity.

Conclusions

The fucose-captured strategy provides a reliable, as well as rapid and convenient, approach for the isolation of tumor-derived exosomes from serum. A four-fucosylated exosomal miRNA panel presents good performance for early LUAD diagnosis.
Molecular determinants of outcomes in meningiomas
Authors: Lynes John , Flores-Milan Gabriel , Rubino Sebastian , Arrington John , Macaulay Robert , Liu James K. C. , Beer-Furlan Andre , Tran Nam D. , Vogelbaum Michael A. , Etame Arnold B.
Published: August 2022

Meningiomas are the most common intracranial primary tumor in adults. Surgery is the predominant therapeutic modality for symptomatic meningiomas. Although the majority of meningiomas are benign, there exists a subset of meningiomas that are clinically aggressive. Recent advances in genetics and epigenetics have uncovered molecular alterations that drive tumor meningioma biology with prognostic and therapeutic implications. In this review, we will discuss the advances on molecular determinants of therapeutic response in meningiomas to date and discuss findings of targeted therapies in meningiomas.
HMOX1 promotes lung adenocarcinoma metastasis by affecting macrophages and mitochondrion complexes
Authors: Chen Bo , Zhang Liyang , Zhou Hongshu , Ye Wenrui , Luo Cong , Yang Liting , Fang Ning , Tang Anliu
Published: August 2022

Background

Metastasis is the leading cause of lung adenocarcinoma (LUAD) patient death. However, the mechanism of metastasis is unclear. We performed bioinformatic analyses for HMOX1 (Heme oxygenase-1), aiming to explore its role in LUAD metastasis.

Methods

Pan-cancer analysis was first used to identify the metastasis-associated role of HMOX1 in LUAD. HMOX1-related genomic alterations were then investigated. Based on functional enrichment, we systematically correlated HMOX1 with immunological characteristics and mitochondrial activities. Furthermore, weighted gene co-expression network analysis (WGCNA) was applied to construct the HMOX1-mediated metastasis regulatory network, which was then validated at the proteomic level. Finally, we conducted the survival analysis and predicted the potential drugs to target the HMOX1 network.

Results

HMOX1 expression was significantly associated with epithelial-mesenchymal transition (EMT) and lymph and distant metastasis in LUAD. High HMOX1 levels exhibited higher macrophage infiltration and lower mitochondrial complex expression. WGCNA showed a group of module genes co-regulating the traits mentioned above. Subsequently, we constructed an HMOX1-mediated macrophage-mitochondrion-EMT metastasis regulatory network in LUAD. The network had a high inner correlation at the proteomic level and efficiently predicted prognosis. Finally, we predicted 9 potential drugs targeting HMOX1-mediated metastasis in LUAD, like chloroxine and isoliquiritigenin.

Conclusions

Our analysis elaborates on the role of HMOX1 in LUAD metastasis and identified a highly prognostic HMOX1-mediated metastasis regulatory network. Novel potential drugs targeting the HMOX1 network were also proposed, which should be tested for their activity against LUAD metastasis in future studies.
Exogenous Urokinase Inhibits Proteasomal Degradation of Its Cognate Urokinase Plasminogen Activator Receptor
Authors: Zhu Ran , Liu Ting-Wei , Liu Fan
Published: August 2022

Acute pulmonary embolism (APE) is a debilitating condition with high incidence and mortality rates. APE is widely treated with the serine protease urokinase or urokinase-type plasminogen activator (uPA) that functions by resolving blood clots via catalyzing the conversion of plasminogen to plasmin. Treatment with recombinant uPA has been shown to increase endogenous expression of uPA and its cognate receptor, uPAR; however, the mechanisms for this induction are not known. Using an in vitro hypoxia/reoxygenation model in bronchial epithelial BEAS-2B cells, we show that induction of hypoxia/reoxygenation induces apoptosis and increases secretion of tumor necrosis factor–alpha, brain natriuretic peptide, and fractalkine, which are attenuated when treated with exogenous uPA. Induction of hypoxia/reoxygenation resulted in decreased expression of uPAR on cell surface without any significant changes in its messenger RNA expression, highlighting post-transcriptional regulatory mechanisms. Determination of uPAR protein half-life using cycloheximide showed treatment with uPA significantly increased its half-life (209.6 ± 0.2 min from 48.2 ± 2.3 min). Hypoxia/reoxygenation promoted the degradation of uPAR. Inhibition of proteasome-mediated degradation using MG-132 and lactacystin revealed that uPAR was actively degraded when hypoxia/reoxygenation was induced and that it was reversed when treated with exogenous uPA. Determination of the proteolytic activity of 20S proteasome showed a global increase in ubiquitin–proteasome activation without an increase in proteasome content in cells subjected to hypoxia/reoxygenation. Our results cumulatively reveal that uPAR is actively degraded following hypoxia/reoxygenation, and the degradation was significantly weakened by exogenous uPA treatment. Given the importance of the uPA/uPAR axis in a multitude of pathophysiological contexts, these findings provide important yet undefined mechanistic insights.
Investigation of the mechanism of the anti-cancer effects of Astragalus propinquus Schischkin and Pinellia pedatisecta Schott (A&P) on melanoma via network pharmacology and experimental verification
Authors: Wang Fang , Bai Juan , Li Feng , Liu Jing , Wang Yanli , Li Ning , Wang Yaqi , Xu Jin , Liu Wanbao , Xu Liting , Chen Lin
Published: August 2022

Melanoma is a commonly malignant cutaneous tumor in China. Astragalus propinquus Schischkin and Pinellia pedatisecta Schott (A&P) have been clinically used as adjunctive drugs in the treatment of malignant melanoma. However, the effect and mechanism of A&P on melanoma have yet to be explored. The current investigation seeks to characterize the active components of A&P and their potential roles in treating malignant melanoma using network pharmacology and in vitro and in vivo experiments. We first used the traditional Chinese medicine systems pharmacology (TCMSP) database and high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) to identify a total of 13 effective compounds within A&P. 70 common genes were obtained by matching 487 potential genes of A&P with 464 melanoma-related genes, and then we built up protein-protein interaction (PPI) network of these 70 genes, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. The results revealed that A&P might influence the pathobiology of melanoma through the PI3K/Akt pathway. Molecular docking also confirmed that higher content of ingredients in A&P, including hederagenin, quercetin, beta-sitosterol and stigmasterol, had a strong binding activity (affinity < −5 kcal/mol) with the core targets AKT1, MAPK3 and ESR1. Furthermore, we confirmed A&P could inhibit melanoma cells proliferation and induce cells apoptosis through suppressing the PI3K/Akt signaling pathway by in vitro and in vivo xenograft model experiments. These findings indicate that A&P may function as a useful therapy for melanoma through the PI3K/Akt pathway.
Kanglaite (Coix Seed Extract) as Adjunctive Therapy in Cancer: Evidence Mapping Overview Based on Systematic Reviews With Meta-Analyses
Authors: Lu Cuncun , Wu Shuilin , Ke Lixin , Liu Fumei , Shang Wenru , Deng Xiuxiu , Huang Yanli , Zhang Qiang , Cui Xin , Mentis Alexios-Fotios A. , Xie Yanming , Wang Zhifei
Published: August 2022

Background: Several quantitative systematic reviews of Kanglaite (KLT), an herb preparation used to treat cancer and malignant pleural effusion, have been published in recent years. However, the clinical evidence reported in these studies has not been pursued further and the methodological quality of these meta-analyses remains unknown. Therefore, an overview was designed to map the evidence landscape based on the published meta-analyses on KLT in cancer treatment.

Methods: Two bibliographic databases (PubMed and Embase) were searched from inception to 25 November 2021. Two independent reviewers were involved in study selection, data abstraction, and methodological quality assessment using AMSTAR 2. The principal features of publications and the clinical outcomes of efficacy and safety were synthesized narratively, and results of methodological quality were reported as frequencies and percentages with the corresponding 95% confidence intervals. The evidence map was used to visualize the overall quality. Excel 2016 and Stata 17/SE were used for data analysis.

Results: Thirteen meta-analyses published in English were included for in-depth analysis. Among them, the year of publication ranged from 2008 to 2021, and the number of included patients ranged from 488 to 2,964. Regarding the cancer type, seven articles focused on non-small cell lung cancer, two on malignant pleural effusion, and four reviews on digestive system malignancies, such as hepatocellular carcinoma and pancreatic cancer. Almost all included meta-analyses reported that KLT as adjunctive therapy could improve various efficacy outcomes (such as disease response rates, quality of life, immune indicators) and reduce the rate of occurrence of adverse reactions, such as nausea and vomiting, leukopenia, and anemia. In terms of their methodological quality, three meta-analyses were of low quality, whereas 10 studies were critically low in quality. The methodological flaws main involved items 2 (“predesigned protocol and registration informatio’’), 3 (“rationale of study design for inclusion”), 4 (“comprehensive search strategy’’), 5 (“literature selection in duplicate’’), 7 (“list of excluded studies with reasons’’), 8 (“adequate information on included studies’’), 10 (“funding support for included primary studies’’), and 12 (“evaluation of the potential impact of risk of bias’’) based on the AMSTAR 2 tool.

Conclusion: Current evidence reveals that KLT is effective and safe as an adjunctive treatment for non-small cell lung cancer, malignant pleural effusion, and digestive system malignancies (such as hepatocellular carcinoma). However, the results assessed in this overview should be further verified using well-designed and clearly reported clinical trials and meta-analyses of KLT.
Ninjinyoeito improves social behavior disorder in neuropeptide Y deficient zebrafish
Authors: Kawabe Momoko , Nishida Takumi , Horita Chihoko , Ikeda Asami , Takahashi Ryuji , Inui Akio , Shiozaki Kazuhiro
Published: August 2022

Sociability is an essential component of the linkage structure in human and other vertebrate communication. Low sociability is defined as a poor social approach, including social withdrawal and apathy, and is implicated in a variety of psychiatric disorders. Ninjinyoeito (NYT), a traditional Japanese herbal medicine, has been used in the medical field. This study aimed to determine the effect of NYT on low sociality in NPY-KO zebrafish. NPY-KO zebrafish were fed a 3% NYT-supplemented diet for 4 days and subjected to behavioral tests. In the mirror test, NPY-KO zebrafish fed a control diet showed avoidance behavior toward their mirror counterparts. In contrast, the treatment of NPY-KO zebrafish with NYT significantly increased their interaction with their counterparts in the mirror. In addition, a 3-chambers test was conducted to confirm the effect of NYT on the low sociality of NPY-KO zebrafish. NPY-KO zebrafish fed the control diet showed less interaction with fish chambers, while NYT treatment increased the interaction. Phosphorylation of ERK, a marker of neuronal activity, was significantly reduced in the whole brain of NYT-fed NPY-KO zebrafish, compared to the control diet. NYT treatment significantly suppressed hypothalamic-pituitary-adrenal-related genes (gr, pomc, and crh) and sympathetic-adrenal-medullary-related genes (th1, th2, and cck) in NPY-KO zebrafish. NYT administration significantly reduced mRNA levels of gad1b compared to the control diet, suggesting the involvement of GABAergic neurons in NYT-induced improvement of low sociability. Furthermore, the expression of CREB was suppressed when NPY-KO zebrafish were fed NYT. Next, we attempted to identify the effective herb responsible for the NYT-induced improvement of low sociability. NPY-KO zebrafish were fed an experimental diet containing the target herb for 4 days, and its effect on sociability was evaluated using the 3-chambers test. Results showed that Cinnamon Bark and Polygala Root treatments significantly increased time spent in the fish tank area compared to the control diet, while the other 10 herbs did not. We confirmed that these two herbs suppressed the activity of HPA-, SAM-, and GABAergic neurons, as well as NYT-treated zebrafish, accompanied by downregulation of CREB signaling. This study suggests the potential use of NYT as a drug for sociability disorders.
Inhibitory effect of (pro)renin receptor decoy inhibitor PRO20 on endoplasmic reticulum stress during cardiac remodeling
Authors: Zhang Jing , Cheng Yun-Jiu , Luo Chang-Jun , Yu Jia
Published: August 2022

Background: Ectopic activation of renin-angiotensin-system contributes to cardiovascular and renal diseases. (Pro)renin receptor (PRR) binds to renin and prorenin, participating in the progression of nephrology. However, whether PRR could be considered as a therapeutic target for cardiac remodeling and heart failure remains unknown.

Materials and methods: Transverse aortic constriction (TAC) surgery was performed to establish a mouse model of chronic pressure overload-induced cardiac remodeling. Neonatal rat cardiomyocytes (CMs) and cardiac fibroblasts (CFs) were isolated and stimulated by Angiotensin II (Ang II). PRR decoy inhibitor PRO20 was synthesized and used to evaluate its effect on cardiac remodeling.

Results: Soluble PRR and PRR were significantly upregulated in TAC-induced cardiac remodeling and Ang II-treated CMs and CFs. Results of In vivo experiments showed that suppression of PRR by PRO20 significantly retarded cardiac remodeling and heart failure indicated by morphological and echocardiographic analyses. In vitro experiments, PRO20 inhibited CM hypertrophy, and also alleviated CF activation, proliferation and extracellular matrix synthesis. Mechanically, PRO20 enhanced intracellular cAMP levels, but not affected cGMP levels in CMs and CFs. Moreover, treatment of PRO20 in CFs markedly attenuated the production of reactive oxygen species and phosphorylation of IRE1 and PERK, two well-identified markers of endoplasmic reticulum (ER) stress. Accordingly, administration of PRO20 reversed ER stressor thapsigargin-induced CM hypertrophy and CF activation/migration.

Conclusion: Taken together, these findings suggest that inhibition of PRR by PRO20 attenuates cardiac remodeling through increasing cAMP levels and reducing ER stress in both CMs and CFs.
Hesperidin promotes gastric motility in rats with functional dyspepsia by regulating Drp1-mediated ICC mitophagy
Authors: Jia Qingling , Li Li , Wang Xiangxiang , Wang Yujiao , Jiang Kailin , Yang Keming , Cong Jun , Cai Gan , Ling Jianghong
Published: August 2022

Hesperidin is one of the main active ingredients of Citrus aurantiumL. (Rutaceae) and tangerine peel, which have anti-inflammatory and antioxidant effects. In previous study, we found that gastric motility disorder in functional dyspepsia (FD) rats accompanied by excessive autophagy/mitochondrial swelling and even vacuolization in the interstitial cells of cajal (ICC), but the exact mechanism has not yet been investigated. Therefore, we used different doses of hesperidin (50 mg/kg, 100 mg/kg, and 200 mg/kg) to intervene in FD rats, and found that medium doses of hesperidin (100 mg/kg) significantly increased gastric motility in FD rats. Subsequently, FD rats were randomly divided into control group, model group, mdivi-1 group, mdivi-1+hesperidin group and hesperidin group, and mitochondrial division inhibitor (mdivi-1) was injected intraperitoneally to further investigate whether hesperidin could regulate dynamin-related protein 1 (Drp1)-mediated mitophagy in ICC to improve mitochondrial damage. The results showed that compared with the model group, the serum malondialdehyde (MDA) level decreased and the superoxide dismutase (SOD) level increased in the mdivi-1 and hesperidin groups (p < 0.001). Transmission electron microscopy (TEM) observed that the mitochondrial nuclear membrane was intact in gastric tissues with a clear internal cristae pattern, and autophagy lysosomes were rare. The co-localization expression of microtubule associated protein 1 light chain 3 (LC3) and voltage dependent anion channel 1 (VDAC1), Drp1 and translocase of the outer mitochondrial membrane 20 (Tom20) was significantly decreased (p < 0.001), the protein expression of mitochondrial Drp1, Beclin1 and LC3 were significantly decreased (p < 0.001), the protein expression of mitochondrial P62 and ckit in gastric tissue were significantly increased (p < 0.05, p < 0.001). The above situation was improved more significantly by the synergistic intervention of mdivi-1 and hesperidin. Therefore, hesperidin can improve mitochondrial damage and promote gastric motility in FD rats by regulating Drp1-mediated ICC mitophagy.
Up-and-coming anti-epileptic effect of aloesone in Aloe vera: Evidenced by integrating network pharmacological analysis, in vitro, and in vivo models
Authors: Wang Yan , Li Chang , Xiong Zhongyv , Chen Niangen , Wang Xuesong , Xu Junyv , Wang Yuemei , Liu Longfeng , Wu Hang , Huang Caihui , Huang Aiqin , Tan Jiajia , Li Youbin , Li Qifu
Published: August 2022

Background:Aloe vera is a medically valuable plant with anti-epileptic activity; however, its mechanism of action remains unknown. In this study, network pharmacological, in vitro, and in vivo experiments were carried out to explore the potential anti-epileptic components and targets of Aloe vera.

Methods: The main active components of Aloe vera were identified by searching the Traditional Chinese Medicine System Pharmacology database. Targets of Aloe vera were predicted using SwissTargetPrediction, whereas information about the epilepsy disease targets was obtained from Gene Cards. The protein–protein interaction network and core targets were screened according to the topological structure and CytoNCA plugin. The glutamate-induced HT22 cell line and pentylenetetrazol-induced seizure rats were used to confirm the effect of aloesone by detecting reactive oxygen species (ROS) and apoptosis, and predicting the targets.

Results: A total of 14 core active components were selected based on the screening criteria of oral bioavailability ≥30% and drug-likeness ≥ 0.10. Four compounds, namely linoleic acid, aloesone, isoeleutherol glucosiden qt, and anthranol, demonstrated the potential ability of crossing the blood-brain barrier. A total of 153 targets associated with epilepsy were predicted for the four compounds. Moreover, after network analysis with CytoNCA, 10 targets, namely, MAPK1, SRC, MARK3, EGFR, ESR1, PTGS2, PTPN11, JAK2, PPKCA, and FYN, were selected as the core genes, and SRC, which has been predicted to be the target of aloesone and anthranol, exhibited the highest subgraph centrality value. In vitro experiments confirmed that aloesone treatment significantly inhibited the glutamate-induced neuronal injury by reducing the intracellular ROS content and the early phase of apoptosis. Additionally, treatment with 50 mg/kg aloesone resulted in anti-seizure effects by reducing the seizure score and prolonging the latent period in acute and chronic rats. Furthermore, aloesone treatment increased the phosphorylation of c-SRC at Y418 and reduced the phosphorylation at Y529, simultaneously activating c-SRC.

Conclusion: Integrating network pharmacology with in vitro and in vivo experiments demonstrated that aloesone, which inhibited seizure by activating c-SRC, is a potential anti-seizure compound present in Aloe vera.