bluuebunny/crossref_metadata_2025 huggingface dataset:
Dysfunction of the Glymphatic System as a Potential Mechanism of Perioperative Neurocognitive Disorders
Authors: Ren Xuli , Liu Shan , Lian Chuang , Li Haixia , Li Kai , Li Longyun , Zhao Guoqing
Published: June 2021

Perioperative neurocognitive disorder (PND) frequently occurs in the elderly as a severe postoperative complication and is characterized by a decline in cognitive function that impairs memory, attention, and other cognitive domains. Currently, the exact pathogenic mechanism of PND is multifaceted and remains unclear. The glymphatic system is a newly discovered glial-dependent perivascular network that subserves a pseudo-lymphatic function in the brain. Recent studies have highlighted the significant role of the glymphatic system in the removal of harmful metabolites in the brain. Dysfunction of the glymphatic system can reduce metabolic waste removal, leading to neuroinflammation and neurological disorders. We speculate that there is a causal relationship between the glymphatic system and symptomatic progression in PND. This paper reviews the current literature on the glymphatic system and some perioperative factors to discuss the role of the glymphatic system in PND.
Impaired Executive Function and Depression as Independent Risk Factors for Reported Delirium Symptoms: An Observational Cohort Study Over 8 Years
Authors: Mychajliw Christian , Herrmann Matthias L. , Suenkel Ulrike , Brand Katharina , von Thaler Anna-Katharina , Wurster Isabel , Yilmaz Rezzak , Eschweiler Gerhard W. , Metzger Florian G.
Published: June 2021

Background

Acute medical illnesses, surgical interventions, or admissions to hospital in older individuals are frequently associated with a delirium. In this cohort study, we investigated the impact of specific cognitive domains and depression before the occurrence of delirium symptoms in an 8-year observation of older non-hospitalized individuals.

Methods

In total, we included 807 participants (48–83 years). Deficits in specific cognitive domains were measured using the CERAD test battery, and depressive symptoms were measured using Beck Depression Inventory and the Geriatric Depression Scale (GDS) before the onset of a delirium. Delirium symptoms were retrospectively assessed by a questionnaire based on the established Nursing Delirium Screening Scale.

Results

Fifty-eight of eight hundred seven participants (7.2%) reported delirium symptoms over the 8-year course of the study. Sixty-nine percent (n = 40) of reported delirium symptoms were related to surgeries. In multivariate regression analysis, impaired executive function was an independent risk factor (p = 0.034) for the occurrence of delirium symptoms. Furthermore, age (p = 0.014), comorbidities [captured by the Charlson Comorbidity Index (CCI)] (p < 0.001), and depression (p = 0.012) were significantly associated with reported delirium symptoms.

Conclusion

Especially prior to elective surgery or medical interventions, screening for impaired executive function and depression could be helpful to identify patients who are at risk to develop delirium symptoms.
Effects of Prenatal Alcohol Exposure on the Volumes of the Lateral and Medial Walls of the Intraparietal Sulcus
Authors: Miles Marlie , Warton Fleur L. , Meintjes Ernesta M. , Molteno Christopher D. , Jacobson Joseph L. , Jacobson Sandra W. , Warton Christopher M. R.
Published: June 2021

Fetal alcohol spectrum disorders (FASD) continue to be the leading preventable cause of intellectual disability in the U.S., Europe, and in endemic areas, such as the Western Cape region of South Africa. Arithmetic is highly sensitive to prenatal alcohol exposure (PAE). The intraparietal sulcus (IPS) is known to play a critical role in number processing. In this study, we investigate whether smaller IPS volumes play a role in the number-processing deficits observed in children with PAE. Participants were 52 9- to 14-year-old children from a historically disadvantaged community in Cape Town, who are participating in our ongoing studies on the effects of PAE on the brain. The IPS was manually parcellated into its medial (MIPS) and lateral (LIPS) walls on magnetic resonance images. The study aimed to examine: (1) the effects of PAE on IPS regional volumes and asymmetry, (2) whether IPS regional volumes are related to number processing performance and, if so, whether these relations are moderated by PAE and (3) potential mediation by regional IPS volumes of the relation between PAE and number processing performance. Total intracranial volume (TIV) was associated with volumes in all regions except the right LIPS. Both left MIPS and left LIPS volumes were significantly smaller in children in the fetal alcohol syndrome (FAS)/partial FAS (PFAS) group compared to controls. The finding in the left LIPS remained significant after controlling for potential confounders and after adjustment for the smaller overall brain size of the children in the FAS/PFAS group. Smaller left LIPS volumes in the FAS/PFAS group may account for the absence of left-right asymmetry in the LIPS in children with FAS/PFAS compared to controls and nonsyndromal heavily exposed (HE) children. Bilaterally, larger MIPS volumes were associated with better WISC IQ Arithmetic scores. These effects, however, were not moderated by the degree of PAE, and regional IPS volumes did not mediate the effect of PAE on WISC Arithmetic scores. Although we found that certain regions of the IPS were smaller in children with FAS and PFAS, these PAE-induced changes in IPS volume did not mediate the alcohol-related deficits in arithmetic.
Potential and Realized Impact of Astroglia Ca2 + Dynamics on Circuit Function and Behavior
Authors: Lim Eunice Y. , Ye Liang , Paukert Martin
Published: June 2021

Astroglia display a wide range of spontaneous and behavioral state-dependent Ca2+ dynamics. During heightened vigilance, noradrenergic signaling leads to quasi-synchronous Ca2+ elevations encompassing soma and processes across the brain-wide astroglia network. Distinct from this vigilance-associated global Ca2+ rise are apparently spontaneous fluctuations within spatially restricted microdomains. Over the years, several strategies have been pursued to shed light on the physiological impact of these signals including deletion of endogenous ion channels or receptors and reduction of intracellular Ca2+ through buffering, extrusion or inhibition of release. Some experiments that revealed the most compelling behavioral alterations employed chemogenetic and optogenetic manipulations to modify astroglia Ca2+ signaling. However, there is considerable contrast between these findings and the comparatively modest effects of inhibiting endogenous sources of Ca2+. In this review, we describe the underlying mechanisms of various forms of astroglia Ca2+ signaling as well as the functional consequences of their inhibition. We then discuss how the effects of exogenous astroglia Ca2+ modification combined with our knowledge of physiological mechanisms of astroglia Ca2+ activation could guide further refinement of behavioral paradigms that will help elucidate the natural Ca2+-dependent function of astroglia.
Understanding the Impact of Neural Variations and Random Connections on Inference
Authors: Zeng Yuan , Ferdous Zubayer Ibne , Zhang Weixiang , Xu Mufan , Yu Anlan , Patel Drew , Post Valentin , Guo Xiaochen , Berdichevsky Yevgeny , Yan Zhiyuan
Published: June 2021

Recent research suggests that in vitro neural networks created from dissociated neurons may be used for computing and performing machine learning tasks. To develop a better artificial intelligent system, a hybrid bio-silicon computer is worth exploring, but its performance is still inferior to that of a silicon-based computer. One reason may be that a living neural network has many intrinsic properties, such as random network connectivity, high network sparsity, and large neural and synaptic variability. These properties may lead to new design considerations, and existing algorithms need to be adjusted for living neural network implementation. This work investigates the impact of neural variations and random connections on inference with learning algorithms. A two-layer hybrid bio-silicon platform is constructed and a five-step design method is proposed for the fast development of living neural network algorithms. Neural variations and dynamics are verified by fitting model parameters with biological experimental results. Random connections are generated under different connection probabilities to vary network sparsity. A multi-layer perceptron algorithm is tested with biological constraints on the MNIST dataset. The results show that a reasonable inference accuracy can be achieved despite the presence of neural variations and random network connections. A new adaptive pre-processing technique is proposed to ensure good learning accuracy with different living neural network sparsity.
Nerve Growth Factor Enhances Tooth Mechanical Hyperalgesia Through C-C Chemokine Ligand 19 in Rats
Authors: Guo Rui , Chen Yiyin , Liu Lu , Wen Jing , Yang Hong , Zhu Yafen , Gao Meiya , Liang Hengyan , Lai Wenli , Long Hu
Published: June 2021

The nerve growth factor (NGF) plays an important role in the regulation of neuropathic pain. It has been demonstrated that calcitonin gene-related peptide (CGRP), a well-known contributor to neurogenic inflammation, increases neuroinflammatory pain induced by NGF. The inflammatory mediator that NGF most strongly induces is C-C chemokine ligand 19 (CCL19), which can recruit inflammatory cells by binding to the receptor CCR7 followed by promoting the response of neuroinflammation. However, the regulatory mechanism of NGF and CCL19 in tooth movement orofacial pain and the interaction between both are still unclear. In this study, male Sprague–Dawley rats were used to study the modulation of NGF on orofacial pain through CCL19 and the role of each in tooth movement pain in rats. The expression levels of CCL19 mRNA and protein were determined by real-time PCR and immunofluorescence, respectively. Pain levels were assessed by measuring the rats' bite force, which drops as pain rises. Meanwhile, by verifying the relationship between CGRP and CCL19, it was laterally confirmed that NGF could modulate tooth movement-induced mechanical hyperalgesia through CCL19. The results showed that the expression level of CCL19 rose with the increased NGF, and neurons expressing CGRP can express stronger CCL19. Compared with the baseline level, the bite force for all rats dropped sharply on day 1, reached its lowest level on day 3, and recovered gradually on day 5. All results indicated that NGF played an important role in tooth movement orofacial pain via positively regulating CCL19 expression in the trigeminal ganglia of rats. Additionally, CCL19 increased the sensitivity to experimental tooth movement orofacial pain. NGF can regulate CCL19 expression, although it may regulate other inflammatory pathways as well. This is the first report on the interactions and modulations of tooth movement orofacial pain by NGF through CCL19 in rats.
Gene and Phenotype Expansion of Unexplained Early Infantile Epileptic Encephalopathy
Authors: Liu Xianyu , Shen Qiyang , Zheng Guo , Guo Hu , Lu Xiaopeng , Wang Xiaoyu , Yang Xiao , Cao Zixuan , Chen Jing
Published: June 2021

Objective: The genetic aetiology of epileptic encephalopathy (EE) is growing rapidly based on next generation sequencing (NGS) results. In this single-centre study, we aimed to investigate a cohort of Chinese children with early infantile epileptic encephalopathy (EIEE).

Methods: NGS was performed on 50 children with unexplained EIEE. The clinical profiles of children with pathogenic variants were characterised and analysed in detail. Conservation analysis and homology modelling were performed to predict the impact of STXBP1 variant on the protein structure.

Results: Pathogenic variants were identified in 17 (34%) of 50 children. Sixteen variants including STXBP1 (n = 2), CDKL5 (n = 2), PAFAH1B1, SCN1A (n = 9), SCN2A, and KCNQ2 were de novo, and one (PIGN) was a compound heterozygous variant. The phenotypes of the identified genes were broadened. PIGN phenotypic spectrum may include EIEE. The STXBP1 variants were predicted to affect protein stability.

Significance: NGS is a useful diagnostic tool for EIEE and contributes to expanding the EIEE-associated genotypes. Early diagnosis may lead to precise therapeutic interventions and can improve the developmental outcome.
Novel Volumetric and Surface-Based Magnetic Resonance Indices of the Aging Brain – Does Male and Female Brain Age in the Same Way?
Authors: Podgórski Przemysław , Bladowska Joanna , Sasiadek Marek , Zimny Anna
Published: June 2021

Introduction: Novel post-processing methods allow not only for assessment of brain volumetry or cortical thickness based on magnetic resonance imaging (MRI) but also for more detailed analysis of cortical shape and complexity using parameters such as sulcal depth, gyrification index, or fractal dimension. The aim of this study was to analyze changes in brain volumetry and other cortical indices during aging in men and women.

Material and Methods: Material consisted of 697 healthy volunteers (aged 38–80 years; M/F, 264/443) who underwent brain MRI using a 1.5-T scanner. Voxel-based volumetry of total gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) was performed followed by assessment of cortical parameters [cortical thickness (CT), sulcal depth (SD), gyrification index (GI), and fractal dimension (FD)] in 150 atlas locations using surface-based morphometry with a region-based approach. All parameters were compared among seven age groups (grouped every 5 years) separately for men and women. Additionally, percentile curves for men and women were provided for total volumes of GM, WM, and CSF.

Results: In men and women, a decrease in GM and WM volumes and an increase in CSF volume seem to progress slowly since the age of 45. In men, significant GM and WM loss as well as CSF increase start above 55 years of age, while in women, significant GM loss starts above 50 and significant WM loss as well as CSF increase above 60. CT was found to significantly decrease with aging in 39% of locations in women and in 36% of locations in men, SD was found to increase in 13.5% of locations in women and in 1.3% of locations in men, GI was decreased in 3.4% of locations in women and in 2.0% of locations in men, and FD was changed in 2.7% of locations in women compared to 2.0% in men.

Conclusions: Male and female brains start aging at the similar age of 45. Compared to men, in women, the cortex is affected earlier and in the more complex pattern regarding not only cortical loss but also other alterations within the cortical shape, with relatively longer sparing of WM volume.
Immunotherapies for Neurodegenerative Diseases
Authors: Mortada Ibrahim , Farah Raymond , Nabha Sanaa , Ojcius David M. , Fares Youssef , Almawi Wassim Y. , Sadier Najwane Said
Published: June 2021

The current treatments for neurodegenerative diseases are mostly symptomatic without affecting the underlying cause of disease. Emerging evidence supports a potential role for immunotherapy in the management of disease progression. Numerous reports raise the exciting prospect that either the immune system or its derivative components could be harnessed to fight the misfolded and aggregated proteins that accumulate in several neurodegenerative diseases. Passive and active vaccinations using monoclonal antibodies and specific antigens that induce adaptive immune responses are currently under evaluation for their potential use in the development of immunotherapies. In this review, we aim to shed light on prominent immunotherapeutic strategies being developed to fight neuroinflammation-induced neurodegeneration, with a focus on innovative immunotherapies such as vaccination therapy.
Relationships Between D-Dimer Levels and Stroke Risk as Well as Adverse Clinical Outcomes After Acute Ischemic Stroke or Transient Ischemic Attack: A Systematic Review and Meta-Analysis
Authors: Yuan Bing , Yang Tong , Yan Tao , Cheng Wenke , Bu Xiancong
Published: June 2021

Objective: Abnormal elevation of D-dimer levels is an important indicator of disseminated intravascular clotting. Therefore, we hypothesized that high D-dimer levels were associated with the risk of stroke and adverse clinical outcomes of patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA).

Methods: The present meta-analysis aimed to systematically analyze the associations between D-dimer and the risk of stroke as well as the clinical outcomes of patients with post-stroke or TIA. Meanwhile, dose–response analyses were conducted when there were sufficient data available. Three electronic databases including Pubmed, the Embase database, and the Cochrane Library were searched by two investigators independently. All the pooled results were expressed as risk ratios (RRs).

Results: Finally, 22 prospective cohort studies were included into this meta-analysis. The results suggested that high D-dimer levels were associated with increased risks of total stroke (RR 1.4, 95%CI 1.20–1.63), hemorrhagic stroke (RR 1.25, 95%CI 0.69–2.25), and ischemic Stroke (RR 1.55, 95%CI 1.22–1.98), and the dose-dependent relationship was not found upon dose–response analyses. Besides, the high D-dimer levels on admission were correlated with increased risks of all-cause mortality [RR 1.77, 95% confidence interval (CI) 1.26–2.49], 5-day recurrence (RR 2.28, 95%CI 1.32–3.95), and poor functional outcomes (RR 2.01, 95%CI 1.71–2.36) in patients with AIS or TIA.

Conclusions: On the whole, high D-dimer levels may be associated with the risks of total stroke and ischemic stroke, but not with hemorrhagic stroke. However, dose–response analyses do not reveal distinct evidence for a dose-dependent association of D-dimer levels with the risk of stroke. Besides, high D-dimer levels on admission may predict adverse clinical outcomes, including all-cause mortality, 5-day recurrence, and 90-day poor functional outcomes, of patients with AIS or TIA. More studies are warranted to quantify the effect of D-dimer levels on the risk of stroke or TIA, so as to verify and substantiate this conclusion in the future.
Post-COVID Opsoclonus Myoclonus Syndrome: A Case Report From Pakistan
Authors: Ishaq Hira , Durrani Talha , Umar Zainab , Khan Nemat , McCombe Pamela , Ul Haq Mian Ayaz
Published: June 2021

Background: Coronavirus disease-2019 (COVID-19), caused by the severe acute respiratory distress syndrome–coronavirus-2 (SARS-CoV-2), is primarily a respiratory infection but has been recently associated with a variety of neurological symptoms. We present herewith a COVID-19 case manifesting as opsoclonus-myoclonus syndrome (OMS), a rare neurological disorder.

Case Presentation: A 63-year-old male diagnosed with COVID-19 infection developed behavioral changes, confusion, and insomnia followed by reduced mobility and abnormal eye movements within 48 h of recovery from respiratory symptoms associated with COVID-19. On examination, he had rapid, chaotic, involuntary saccadic, multidirectional eye movements (opsoclonus), and limb myoclonus together with truncal ataxia. CSF analysis, MRI of the brain, and screening for anti-neuronal and encephalitis related antibodies were negative. Extensive testing revealed no underlying malignancy. The patient was successfully treated with intravenous immunoglobulin (IVIG) with complete resolution of symptoms within 4 weeks of treatment.

Conclusion: COVID-19 infection can be associated with the manifestation of opsoclonus myoclonus syndrome, a rare neurological disorder that can be treated with IVIG if not responsive to corticosteroids.
Altered Sleep-Related Consolidation and Neurocognitive Comorbidity in CECTS
Authors: Georgopoulou Victoria , Spruyt Karen , Garganis Kyriakos , Kosmidis Mary H.
Published: June 2021

Our aim is to use neurophysiological sleep-related consolidation (SRC) phenomena to identify putative pathophysiological mechanisms in CECTS linked to diffuse neurocognitive deficits. We argue that there are numerous studies on the association between seizure aspects and neurocognitive functioning but not as many on interictal variables and neurocognitive deficits. We suggest two additional foci. First, the interictal presentation in CECTS and second, neuronal oscillations involved in SRC processes. Existing data on mechanisms through which interictal epileptiform spikes (IES) impact upon SRC indicate that they have the potential to: (a) perturb cross-regional coupling of neuronal oscillations, (b) mimic consolidation processes, (c) alter the precision of the spatiotemporal coupling of oscillations, and (d) variably impact upon SRC performance. Sleep spindles merit systematic study in CECTS in order to clarify: (a) the state of the slow oscillations (SOs) with which they coordinate, (b) the precision of slow oscillation-spindle coupling, and (c) whether their developmental trajectories differ from those of healthy children. We subsequently review studies on the associations between IES load during NREM sleep and SRC performance in childhood epilepsy. We then use sleep consolidation neurophysiological processes and their interplay with IES to help clarify the diffuse neurocognitive deficits that have been empirically documented in CECTS. We claim that studying SRC in CECTS will help to clarify pathophysiological mechanisms toward diverse neurocognitive deficits. Future developments could include close links between the fields of epilepsy and sleep, as well as new therapeutic neurostimulation targets. At the clinical level, children diagnosed with CECTS could benefit from close monitoring with respect to epilepsy, sleep and neurocognitive functions.
Contrast and Conflict in Dutch Vowels
Authors: de Rue Nadine P. W. D. , Snijders Tineke M. , Fikkert Paula
Published: June 2021

The nature of phonological representations has been extensively studied in phonology and psycholinguistics. While full specification is still the norm in psycholinguistic research, underspecified representations may better account for perceptual asymmetries. In this paper, we report on a mismatch negativity (MMN) study with Dutch listeners who took part in a passive oddball paradigm to investigate when the brain notices the difference between expected and observed vowels. In particular, we tested neural discrimination (indicating perceptual discrimination) of the tense mid vowel pairs /o/-/ø/ (place contrast), /e/-/ø/ (labiality or rounding contrast), and /e/-/o/ (place and labiality contrast). Our results show (a) a perceptual asymmetry for place in the /o/-/ø/ contrast, supporting underspecification of [CORONAL] and replicating earlier results for German, and (b) a perceptual asymmetry for labiality for the /e/-/ø/ contrast, which was not reported in the German study. A labial deviant [ø] (standard /e/) yielded a larger MMN than a deviant [e] (standard /ø/). No asymmetry was found for the two-feature contrast. This study partly replicates a similar MMN study on German vowels, and partly presents new findings indicating cross-linguistic differences. Although the vowel inventory of Dutch and German is to a large extent comparable, their (morpho)phonological systems are different, which is reflected in processing.
Improving the Effect of Transcranial Alternating Current Stimulation (tACS): A Systematic Review
Authors: Wu Linyan , Liu Tian , Wang Jue
Published: June 2021

With the development of electrical stimulation technology, traditional transcranial alternating current stimulation (tACS) technology has been found to have the drawback of not targeting a specific area accurately. Studies have shown that optimizing the number and position of electrodes during electrical stimulation has a very good effect on enhancing brain stimulation accuracy. At present, an increasing number of laboratories have begun to optimize tACS. However, there has been no study summarizing the optimization methods of tACS. Determining whether different optimization methods are effective and the optimization approach could provide information that could guide future tACS research. We describe the results of recent research on tACS optimization and integrate the optimization approaches of tACS in recent research. Optimization approaches can be classified into two groups: high-definition electrical stimulation and interference modulation electrical stimulation. The optimization methods can be divided into five categories: high-definition tACS, phase-shifted tACS, amplitude-modulated tACS, the temporally interfering (TI) method, and the intersectional short pulse (ISP) method. Finally, we summarize the latest research on hardware useful for tACS improvement and outline future directions.
Brain-Computer Interface Coupled to a Robotic Hand Orthosis for Stroke Patients’ Neurorehabilitation: A Crossover Feasibility Study
Authors: Cantillo-Negrete Jessica , Carino-Escobar Ruben I. , Carrillo-Mora Paul , Rodriguez-Barragan Marlene A. , Hernandez-Arenas Claudia , Quinzaños-Fresnedo Jimena , Hernandez-Sanchez Isauro R. , Galicia-Alvarado Marlene A. , Miguel-Puga Adan , Arias-Carrion Oscar
Published: June 2021

Brain-Computer Interfaces (BCI) coupled to robotic assistive devices have shown promise for the rehabilitation of stroke patients. However, little has been reported that compares the clinical and physiological effects of a BCI intervention for upper limb stroke rehabilitation with those of conventional therapy. This study assesses the feasibility of an intervention with a BCI based on electroencephalography (EEG) coupled to a robotic hand orthosis for upper limb stroke rehabilitation and compares its outcomes to conventional therapy. Seven subacute and three chronic stroke patients (M= 59.9 ± 12.8) with severe upper limb impairment were recruited in a crossover feasibility study to receive 1 month of BCI therapy and 1 month of conventional therapy in random order. The outcome measures were comprised of: Fugl-Meyer Assessment of the Upper Extremity (FMA-UE), Action Research Arm Test (ARAT), motor evoked potentials elicited by transcranial magnetic stimulation (TMS), hand dynamometry, and EEG. Additionally, BCI performance and user experience were measured. All measurements were acquired before and after each intervention. FMA-UE and ARAT after BCI (23.1 ± 16; 8.4 ± 10) and after conventional therapy (21.9 ± 15; 8.7 ± 11) were significantly higher (p< 0.017) compared to baseline (17.5 ± 15; 4.3 ± 6) but were similar between therapies (p> 0.017).ViaTMS, corticospinal tract integrity could be assessed in the affected hemisphere of three patients at baseline, in five after BCI, and four after conventional therapy. While no significant difference (p> 0.05) was found in patients’ affected hand strength, it was higher after the BCI therapy. EEG cortical activations were significantly higher over motor and non-motor regions after both therapies (p< 0.017). System performance increased across BCI sessions, from 54 (50, 70%) to 72% (56, 83%). Patients reported moderate mental workloads and excellent usability with the BCI. Outcome measurements implied that a BCI intervention using a robotic hand orthosis as feedback has the potential to elicit neuroplasticity-related mechanisms, similar to those observed during conventional therapy, even in a group of severely impaired stroke patients. Therefore, the proposed BCI system could be a suitable therapy option and will be further assessed in clinical trials.
Bioinformatics Analysis Identifies Potential Ferroptosis Key Genes in the Pathogenesis of Intracerebral Hemorrhage
Authors: Liu Tongye , Li Xinhe , Cui Yiteng , Meng Pingping , Zeng Guanghui , Wang Qiang , Wang Yuyang
Published: June 2021

Intracerebral hemorrhage (ICH) is a dangerous neurological disease. The mechanism of ferroptosis in ICH remains unclear. Using bioinformatics analysis, we aimed to identify the key molecules involved in ferroptosis and provide treatment targets for ICH to further explore the mechanism of ferroptosis in ICH. GSE24265 was downloaded from the Gene Expression Omnibus (GEO) dataset and intersected with ferroptosis genes. A total of 45 differentially expressed genes (DEGs) were selected, most of which were involved in the TNF signaling pathway and oxidative stress response. Key modules constructed by the protein–protein interaction (PPI) network analysis and screening of genes related to the TNF signaling pathway led to the confirmation of the following genes of interest:MAPK1,MAPK8,TNFAIP3,ATF4, andSLC2A1. Moreover,MAPK1was one of the key genes related to TNF signaling and oxidative stress, and it may play an important role in ferroptosis after cerebral hemorrhage. TheMAPK1-related molecules includedhsa-miR-15b-5P,hsa-miR-93-5P,miR-20b-5p,SNHG16,XIST,AC084219.4,RP11-379K17.11,CTC-444N24.11,GS1-358P8.4,CTB-89H12.4,RP4-773N10.5, andFGD5-AS1.We also generated a hemorrhage rat model, which was used to conduct exercise intervention in ICH rats, and qRT-PCR was used to assess the expression levels of our genes of interest. The mRNA levels after cerebral hemorrhage showed thatMAPK1,ATF4,SLC2A1, andTNFAIP3were upregulated, whereasMAPK8was downregulated. Treadmill training increased the expression of anti-inflammatory moleculesTNFAIP3andSLC2A1and reduced the expression ofMAPK1, ATF4, andMAPK8, indicating that treadmill training may be utilized as antioxidant therapy to decrease neuronal ferroptosis. The results of this study indicated that theMAPK1-related mRNA–miRNA–lncRNA interaction chain could be potentially employed as a biomarker of the inception and progression of ferroptosis after cerebral hemorrhage.
Therapeutic and Improving Function of Lactobacilli in the Prevention and Treatment of Cardiovascular-Related Diseases: A Novel Perspective From Gut Microbiota
Authors: Zhao Xin , Zhong Xinqin , Liu Xiao , Wang Xiaoying , Gao Xiumei
Published: June 2021

The occurrence and development of cardiovascular-related diseases are associated with structural and functional changes in gut microbiota (GM). The accumulation of beneficial gut commensals contributes to the improvement of cardiovascular-related diseases. The cardiovascular-related diseases that can be relieved by Lactobacillus supplementation, including hypercholesterolemia, atherosclerosis, myocardial infarction, heart failure, type 2 diabetes mellitus, and obesity, have expanded. As probiotics, lactobacilli occupy a substantial part of the GM and play important functional roles through various GM-derived metabolites. Lactobacilli ultimately have a beneficial impact on lipid metabolism, inflammatory factors, and oxidative stress to relieve the symptoms of cardiovascular-related diseases. However, the axis and cellular process of gut commensal Lactobacillus in improving cardiovascular-related diseases have not been fully elucidated. Additionally, Lactobacillus strains produce diverse antimicrobial peptides, which help maintain intestinal homeostasis and ameliorate cardiovascular-related diseases. These strains are a field that needs to be further investigated immediately. Thus, this review demonstrated the mechanisms and summarized the evidence of the benefit of Lactobacillus strain supplementation from animal studies and human clinical trials. We also highlighted a broad range of lactobacilli candidates with therapeutic capability by mining their metabolites. Our study provides instruction in the development of lactobacilli as a functional food to improve cardiovascular-related diseases.
EMT and Cancer Cell Stemness Associated With Chemotherapeutic Resistance in Esophageal Cancer
Authors: Liu Xiaojie , He Mingjing , Li Linlin , Wang Xiya , Han Shuhua , Zhao Jinzhu , Dong Yalong , Ahmad Mushtaq , Li Leilei , Zhang Xueyan , Huo Junfeng , Liu Yunfan , Pan Chengxue , Wang Cong
Published: June 2021

Drug resistance often occurs after chemotherapy in esophageal cancer patients, leading to cancer metastasis and recurrence. However, the relationship among cancer cell migration, recurrence and drug resistance in esophageal cancer drug-resistant cells has not been clearly explained. In this study, we constructed paclitaxel (PTX)-resistant esophageal cancer cells to explore the causes of drug resistance and poor prognosis after chemotherapy in esophageal cancer. Colony formation assay was used to evaluate the difference of colony formation between parental cells and drug resistance cells. Microsphere formation assay was used to examine the phenotype of stem cells. Wound healing and Transwell assays were used to detect the migration ability of drug-resistant cells. Western blotting and immunofluorescence assays were used to explore the mechanisms. Finally, we used nude mouse xenograft model to explore the tumor characteristics and the expression of relative proteins to verify our findings in vivo. Our study demonstrated that the cancer cell stemness characteristics exist in drug-resistant esophageal cancer cells, that expressed the biomarkers of stem cells and were prone to epithelial-mesenchymal transition (EMT). Our results suggested that the expression of EMT biomarkers and stemness-related proteins increased in esophageal cancer cells after continuously using chemotherapeutic drugs for a period of time. This study indicated that simultaneously targeting EMT and stemness could be a better strategy for the treatment of esophageal cancer drug resistance.
RuvBL1 Maintains Resistance to TRAIL-Induced Apoptosis by Suppressing c-Jun/AP-1 Activity in Non-Small Cell Lung Cancer
Authors: Li Hao , Zhou Taoran , Zhang Yue , Jiang Hengyi , Zhang Jing , Hua Zichun
Published: June 2021

Lung cancer is the common malignant tumor with the highest death rate in the world. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a potential anticancer agent induces selective apoptotic death of human cancer cells. Unfortunately, approximately half of lung cancer cell lines are intrinsically resistant to TRAIL-induced cell death. In this study, we identified RuvBL1 as a repressor of c-Jun/AP-1 activity, contributing to TRAIL resistance in lung cancer cells. Knocking down RuvBL1 effectively sensitized resistant cells to TRAIL, and overexpression of RuvBL1 inhibited TRAIL-induced apoptosis. Moreover, there was a negative correlation expression between RuvBL1 and c-Jun in lung adenocarcinoma by Oncomine analyses. High expression of RuvBL1 inversely with low c-Jun in lung cancer was associated with a poor overall prognosis. Taken together, our studies broaden the molecular mechanisms of TRAIL resistance and suggest the application of silencing RuvBL1 synergized with TRAIL to be a novel therapeutic strategy in lung cancer treatment.
Promotion of Bone Lesions Through the Myeloma Integrin α6-Mediated Osteolytic Signaling
Authors: Liu Huan , Wang Zhiming , He Jin , Li Zongwei , Gao Jerry Y. , Liu Rui , Lin Pei , Yang Jing
Published: June 2021

Osteolytic destruction is a hallmark of multiple myeloma and impairs myeloma patients’ quality of life. However, the molecular mechanism underlying the pathogenesis of myeloma-associated bone disease remains unclear. In this study, we demonstrate the role of myeloma cell-expressed integrin α6 in bone. Integrin α6 binds to laminin 8 and epidermal growth factor receptor on mesenchymal stem cells (MSCs) to form a trimer complex and upregulates the secretion of osteolytic cytokines from both myeloma cells and MSCs, leading to enhanced bone resorption and reduced bone formation. Thus, this study elucidates an important mechanism for myeloma-induced bone lesions and implicates that targeting integrin α6 may be a viable approach for bone healing in myeloma patients.
Ferroptosis as a New Mechanism in Parkinson’s Disease Therapy Using Traditional Chinese Medicine
Authors: Wu Lijuan , Liu Meijun , Liang Jingtao , Li Nannan , Yang Dongdong , Cai Junjie , Zhang Yong , He Yuan , Chen Zhigang , Ma Tao
Published: June 2021

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. To date, among medications used to treat PD, only levodopa exhibits a limited disease-modifying effect on early-onset PD, but it cannot delay the progression of the disease. In 2018, for the first time, the World Health Organization included traditional Chinese medicine (TCM) in its influential global medical compendium. The use of TCM in the treatment of PD has a long history. At present, TCM can help treat and prevent PD. Iron metabolism is closely associated with PD. Ferroptosis, which is characterized by the accumulation of lipid peroxides, is a recently discovered form of iron-dependent cell death. The research literature indicates that ferroptosis in dopaminergic neurons is an important pathogenetic mechanism of PD. TCM may thus play unique roles in the treatment of PD and provide new ideas for the treatment of PD by regulating pathways associated with ferroptosis.
Patient Explanation of Adherence and Non-Adherence to Venous Leg Ulcer Treatment: A Qualitative Study
Authors: Weller Carolina D. , Richards Catelyn , Turnour Louise , Team Victoria
Published: June 2021

The aim of this study was to understand which factors influence patients’ adherence to venous leg ulcer treatment recommendations in primary care. We adopted a qualitative study design, conducting phone interviews with 31 people with venous leg ulcers in Melbourne, Australia. We conducted 31 semi-structured phone interviews between October and December 2019 with patients with clinically diagnosed venous leg ulcers. Participants recruited to the Aspirin in Venous Leg Ulcer Randomized Control Trial and Cohort study were invited to participate in a qualitative study, which was nested under this trial. We applied the Theoretical Domains Framework to guide the data analysis. The following factors influenced patients’ adherence to venous leg ulcer treatment: understanding the management plan and rationale behind treatment (Knowledge Domain); compression-related body image issues (Social Influences); understanding consequences of not wearing compression (Beliefs about Consequences); feeling overwhelmed because it’s not getting better (Emotions); hot weather and discomfort when wearing compression (Environmental Context and Resources); cost of compression (Environmental Context and Resources); ability to wear compression (Beliefs about Capabilities); patience and persistence (Behavioral Regulation); and remembering self-care instructions (Memory, Attention and Decision Making). The Theoretical Domains Framework was useful for identifying factors that influence patients’ adherence to treatment recommendations for venous leg ulcers management. These factors may inform development of novel interventions to optimize shared decision making and self-care to improve healing outcomes. The findings from this article will be relevant to clinicians involved in management of patients with venous leg ulcers, as their support is crucial to patients’ treatment adherence. Consultation with patients about VLU treatment adherence is an opportunity for clinical practice to be targeted and collaborative. This process may inform guideline development.
Analysis of Models of Doxorubicin-Induced Cardiomyopathy in Rats and Mice. A Modern View From the Perspective of the Pathophysiologist and the Clinician
Authors: Podyacheva Ekaterina Yu , Kushnareva Ekaterina A. , Karpov Andrei A. , Toropova Yana G.
Published: June 2021

Today the pharmacological possibilities of treating cancer are expanding and as a result, life expectancy is increasing against the background of chemotherapy and supportive treatment. In the conditions of successful antitumor treatment, complications associated with its toxic effect on healthy tissues and organs began to come to the fore. Anthracycline cardiomyopathy was the first serious cardiovascular complication to draw the attention of oncologists and cardiologists around the world. Anthracycline drugs such as doxorubicin, epirubicin, idarubicin are still widely used in oncological practice to treat a wide range of solid and hematological malignancies. Doxorubicin-induced cardiomyopathy is closely associated with an increase in oxidative stress, as evidenced by reactive oxygen species (ROS) nduced damage such as lipid peroxidation, and decreased levels of antioxidants. Myofibrillar destruction and dysregulation of intracellular calcium are also important mechanisms, usually associated with doxorubicin-induced cardiotoxicity. Despite the abundance of data on various mechanisms involved in the implementation of doxorubicin-induced cardiotoxicity, a final understanding of the mechanism of the development of doxorubicin cardiomyopathy has not yet been formed. It poses the most significant challenges to the development of new methods of prevention and treatment, as well as to the unambiguous choice of a specific treatment regimen using the existing pharmacological tools. In order to resolve these issues new models that could reflect the development of the chemotherapy drugs effects are needed. In this review we have summarized and analyzed information on the main existing models of doxorubicin cardiomyopathy using small laboratory animals. In addition, this paper discusses further areas of research devoted to the development and validation of new improved models of doxorubicin cardiomyopathy suitable both for studying the mechanisms of its implementation and for the preclinical drugs effectiveness assessment.
Effects of Topical Gabapentin on Ocular Pain and Tear Secretion
Authors: Cammalleri Maurizio , Amato Rosario , Olivieri Melania , Pezzino Salvatore , Bagnoli Paola , Dal Monte Massimo , Rusciano Dario
Published: June 2021

Neuropathic ocular pain is a frequent occurrence in medium to severe dry eye disease (DED). Only palliative treatments, such as lubricants and anti-inflammatory drugs, are available to alleviate patients’ discomfort. Anesthetic drugs are not indicated, because they may interfere with the neural feedback between the cornea and the lacrimal gland, impairing tear production and lacrimation. Gabapentin (GBT) is a structural analog of gamma-amino butyric acid that has been used by systemic administration to provide pain relief in glaucomatous patients. We have already shown in a rabbit model system that its topic administration as eye drops has anti-inflammatory properties. We now present data on rabbits’ eyes showing that indeed GBT given topically as eye drops has analgesic but not anesthetic effects. Therefore, opposite to an anesthetic drug such as oxybuprocaine, GBT does not decrease lacrimation, but–unexpectedly–even stimulates it, apparently through the upregulation of acetylcholine and norepinephrine, and by induction of aquaporin 5 (AQP5) expression in the lacrimal gland. Moreover, data obtainedin vitroon a primary human corneal epithelial cell line also show direct induction of AQP5 by GBT. This suggests that corneal cells might also contribute to the lacrimal stimulation promoted by GBT and participate with lacrimal glands in the restoration of the tear film, thus reducing friction on the ocular surface, which is a known trigger of ocular pain. In conclusion, GBT is endowed with analgesic, anti-inflammatory and secretagogue properties, all useful to treat neuropathic pain of the ocular surface, especially in case of DED.
Methylation Landscape: Targeting Writer or Eraser to Discover Anti-Cancer Drug
Authors: Zhou Wen-min , Liu Bin , Shavandi Amin , Li Lu , Song Hang , Zhang Jian-ye
Published: June 2021

Cancer is a major global health challenge for our health system, despite the important pharmacological and therapeutic discoveries we have seen since past 5 decades. The increasing prevalence and mortality of cancer may be closely related to smoking, exposure to environmental pollution, dietary and genetic factors. Despite significant promising discoveries and developments such as cell and biotechnological therapies a new breakthrough in the medical field is needed to develop specific and effective drugs for cancer treatment. On the development of cell therapies, anti-tumor vaccines, and new biotechnological drugs that have already shown promising effects in preclinical studies. With the continuous enrichment and development of chromatin immunoprecipitation sequencing (ChIP-seq) and its derivative technologies, epigenetic modification has gradually become a research hotspot. As key ingredients of epigenetic modification, Writers, Readers, Erasers have been gradually unveiled. Cancer has been associated with epigenetic modification especially methylation and therefore different epigenetic drugs have been developed and some of those are already undergoing clinical phase I or phase II trials, and it is believed that these drugs will certainly assist the treatment in the near future. With respect to this, an overview of anti-tumor drugs targeting modified enzymes and de-modified enzymes will be performed in order to contribute to future research.
Glucosamine Ameliorates Symptoms of High-Fat Diet-Fed Mice by Reversing Imbalanced Gut Microbiota
Authors: Yuan Xubing , Zheng Junping , Ren Lishi , Jiao Siming , Feng Cui , Du Yuguang , Liu Hongtao
Published: June 2021

Glucosamine (GlcN) is used as a supplement for arthritis and joint pain and has been proved to have effects on inflammation, cancer, and cardiovascular diseases. However, there are limited studies on the regulatory mechanism of GlcN against glucose and lipid metabolism disorder. In this study, we treated high-fat diet (HFD)-induced diabetic mice with GlcN (1 mg/ml, in drinking water) for five months. The results show that GlcN significantly reduced the fasting blood glucose of HFD-fed mice and improved glucose tolerance. The feces of intestinal contents in mice were analyzed using 16s rDNA sequencing. It was indicated that GlcN reversed the imbalanced gut microbiota in HFD-fed mice. Based on the PICRUSt assay, the signaling pathways of glucolipid metabolism and biosynthesis were changed in mice with HFD feeding. By quantitative real-time PCR (qPCR) and hematoxylin and eosin (H&E) staining, it was demonstrated that GlcN not only inhibited the inflammatory responses of colon and white adipose tissues, but also improved the intestinal barrier damage of HFD-fed mice. Finally, the correlation analysis suggests the most significantly changed intestinal bacteria were positively or negatively related to the occurrence of inflammation in the colon and fat tissues of HFD-fed mice. In summary, our studies provide a theoretical basis for the potential application of GlcN to glucolipid metabolism disorder through the regulation of gut microbiota.
Effect of Oxidative Stress on Diaphragm Dysfunction and Exercise Intervention in Chronic Obstructive Pulmonary Disease
Authors: Zhang Bingzhi , Li Peijun , Li Jian , Liu Xiaodan , Wu Weibing
Published: June 2021

Chronic obstructive pulmonary disease (COPD) can cause extrapulmonary injury such as diaphragm dysfunction. Oxidative stress is one of the main factors causing diaphragm dysfunction in COPD. Exercise plays a positive role in the prevention and treatment of diaphragm dysfunction in COPD, and the changes in diaphragm structure and function induced by exercise are closely related to the regulation of oxidative stress. Therefore, on the basis of the review of oxidative stress and the changes in diaphragm structure and function in COPD, this article analyzed the effects of exercise on oxidative stress and diaphragm dysfunction in COPD and explored the possible mechanism by which exercise improves oxidative stress. Studies have found that diaphragm dysfunction in COPD includes the decline of muscle strength, endurance, and activity. Oxidative stress mainly affects the structure and function of the diaphragm in COPD through protein oxidation, protease activation and calcium sensitivity reduction. The effects of exercise on oxidative stress level and diaphragm dysfunction may differ depending on the intensity, duration, and style of exercise. The mechanism of exercise on oxidative stress in the diaphragm of COPD may include improving antioxidant capacity, reducing oxidase activity and improving mitochondrial function.