bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of ROQUIN, Tristetraprolin (TTP), and BDNF/miR-16/TTP regulatory axis in late onset Alzheimer’s disease
Authors: Asadi Mohammad Reza , Talebi Mahnaz , Gharesouran Jalal , Sabaie Hani , Jalaiei Abbas , Arsang-Jang Shahram , Taheri Mohammad , Sayad Arezou , Rezazadeh Maryam
Published: August 2022

Alzheimer’s disease (AD) is a heterogeneous degenerative disorder of the brain that is on the rise worldwide. One of the critical processes that might be disturbed in AD is gene expression regulation. Tristetraprolin (TTP) and RC3H1 gene (ROQUIN) are two RNA-binding proteins (RBPs) that target AU-rich elements (AREs) and constitutive decay elements (CDEs), respectively. TTP and ROQUIN, members of the CCCH zinc-finger protein family, have been demonstrated to fine-tune numerous inflammatory factors. In addition, miR-16 has distinct characteristics and may influence the target mRNA through the ARE site. Interestingly, BDNF mRNA has ARE sites in the 3’ untranslated region (UTR) and can be targeted by regulatory factors, such as TTP and miR-16 on MRE sequences, forming BDNF/miR-16/TTP regulatory axis. A number of two microarray datasets were downloaded, including information on mRNAs (GSE106241) and miRNAs (GSE157239) from individuals with AD and corresponding controls. R software was used to identify BDNF, TTP, ROQUIN, and miR-16 expression levels in temporal cortex (TC) tissue datasets. Q-PCR was also used to evaluate the expression of these regulatory factors and the expression of BDNF in the blood of 50 patients with AD and 50 controls. Bioinformatic evaluation showed that TTP and miR-16 overexpression might act as post-transcriptional regulatory factors to control BDNF expression in AD in TC samples. Instead, this expression pattern was not found in peripheral blood samples from patients with AD compared to normal controls. ROQUIN expression was increased in the peripheral blood of patients with AD. Hsa-miR-16-5p levels did not show significant differences in peripheral blood samples. Finally, it was shown that TTP and BDNF, based on evaluating the receiver operating characteristic (ROC), effectively identify patients with AD from healthy controls. This study could provide a new perspective on the molecular regulatory processes associated with AD pathogenic mechanisms linked to the BDNF growth factor, although further research is needed on the possible roles of these factors in AD.
Exploration of combined physical activity and music for patients with Alzheimer’s disease: A systematic review
Authors: Li Kailimi , Cui CanCan , Zhang Haipeng , Jia Luning , Li Rui , Hu Hao-Yu
Published: August 2022

Objective

Alzheimer’s disease (AD) can be treated in different ways, one of which is combined physical activity and music intervention, which is a non-pharmacological one. This study provided a thorough systematic review on the application of combined physical activity and music intervention in patients with AD.

Method

Online sources, such as PubMed, Web of Science, SAGE Premier, EBSCO, and Cochrane, published from January 2002 to March 2022 were searched for articles. Reviewer screened articles on inclusion criteria and identified relevant studies. 200 studies were selected as potentially relevant; of these, eight met all the inclusion criteria.

Results

The systemic review looked at eight studies, two of which had high methodological quality and six were of moderate quality. Various types of research were included: randomized controlled tails, single-subject study, crossover study, and case report. Music intervention was conducted during an exercise program in six studies. A cognitive stimulation was applied with music therapy and physical activities among two studies. The physical activities or movements included balance training, stretching, strengthening, and different sports activities. Outcome assessment, including the Barthel index in two studies and the functional independence measure, was conducted to evaluate the daily functional score. Mental health was evaluated by Mini-Mental State Examination in three studies.

Conclusion

Combined physical activity and music intervention are beneficial and improve the cognition, function and well-being of patients with AD. Supporting combined physical and music intervention will play a key role in helping clinical guidelines for both physical therapists and music therapists.
Encore: Behavioural animal models of stress, depression and mood disorders
Authors: Petković Aleksa , Chaudhury Dipesh
Published: August 2022

Animal studies over the past two decades have led to extensive advances in our understanding of pathogenesis of depressive and mood disorders. Among these, rodent behavioural models proved to be of highest informative value. Here, we present a comprehensive overview of the most popular behavioural models with respect to physiological, circuit, and molecular biological correlates. Behavioural stress paradigms and behavioural tests are assessed in terms of outcomes, strengths, weaknesses, and translational value, especially in the domain of pharmacological studies.
Endovascular treatment for distal basilar artery occlusion stroke
Authors: Song Jiaxing , Yu Zhou , Wang Jian , Luo Xiaojun , Du Jie , Tian Zhengxuan , Yang Shunyu , Xie Weihua , Peng Yuqi , Mu Jinlin , Zi Wenjie , Huang Shuchun , Yang Mei
Published: August 2022

Background

This study aimed to investigate the clinical outcomes of endovascular treatment (EVT) for distal basilar artery occlusion (BAO) and compare them with the outcomes of standard medical treatment (SMT) in daily clinical practice.

Methods

Patients with distal BAO enrolled in the BASILAR study from January 2014 to May 2019 were included. Differences in clinical outcomes were analyzed using Pearson's chi-square test and multivariable logistic regression. Clinical outcomes were evaluated using the modified Rankin Scale (mRS) score at 90 days, the mortality at 90 days, and the occurrence of symptomatic intracranial hemorrhage within 48 h.

Results

Among the 267 patients with distal BAO (222 patients in the EVT group and 45 patients in the SMT group), compared with the SMT group, the EVT group was associated with a favorable outcome (mRS 0–3; 40.1 vs. 15.6%; aOR 5.44; 95% CI, 1.68–17.66; P = 0.005) and decreased mortality (44.6 vs. 71.1%, aOR 0.32, 95% CI, 0.13–0.77; P = 0.012). In the EVT group, multivariable analysis showed that the initial National Institutes of Health Stroke Scale (NIHSS) score and posterior circulation-Alberta Stroke Program Early CT Score (pc-ASPECTS) were associated with favorable functional outcomes and mortality.

Conclusion

Our study suggests that, compared with SMT, EVT is technically feasible and safe for patients with distal BAO.
Eculizumab for acute relapse of neuromyelitis optica spectrum disorder: Case report
Authors: Chatterton Sophie , Parratt John Douglas Edward , Ng Karl
Published: August 2022

Introduction

Eculizumab has been shown to be an effective and typically well-tolerated medication in the treatment of neuromyelitis optica spectrum disorder (NMOSD) in maintaining disease remission in patients who are aquaporin-4 water channel autoantibody (AQP4-IgG) seropositive. The efficacy of eculizumab in an acute relapse of NMOSD however is still under review.

Case

We describe a 46 year-old female who presented with acute left monocular vision loss on a background of bilateral optic neuritis treated 15 years prior as suspected NMOSD. She had very poor vision from the right eye (6/60). On presentation she was not on any long-term immunosuppressive agents. Her serum was positive for AQP4-IgG and MRI brain and spine demonstrated areas of demyelination in the corpus callosum and thoracic spine. She was treated with high dose intravenous methylprednisolone and underwent plasmapheresis for five consecutive days, but continued to clinically deteriorate with ongoing blindness in her left eye (light perception only). She was subsequently administered eculizumab with weaning oral corticosteroids. Clinically her vision improved to counting fingers and she remains on maintenance eculizumab infusions in the community. At 3 months, there is a steady improvement but still significant loss of central vision from that eye.

Conclusion

The utility of eculizumab in NMOSD may assist with treating acute episodes. This theoretically accords with the mode of action in inhibiting conversion of C5–C5a/b, perhaps arresting the acute inflammatory process in this disease. Given that disease burden and mortality in NMOSD is almost entirely related to relapses, increased use of eculizumab acutely could potentially aid recovery from an attack in very severe attacks, and therefore minimize immediate stepwise accrual of disability.
Cortical tracking of voice pitch in the presence of multiple speakers depends on selective attention
Authors: Brodbeck Christian , Simon Jonathan Z.
Published: August 2022

Voice pitch carries linguistic and non-linguistic information. Previous studies have described cortical tracking of voice pitch in clean speech, with responses reflecting both pitch strength and pitch value. However, pitch is also a powerful cue for auditory stream segregation, especially when competing streams have pitch differing in fundamental frequency, as is the case when multiple speakers talk simultaneously. We therefore investigated how cortical speech pitch tracking is affected in the presence of a second, task-irrelevant speaker. We analyzed human magnetoencephalography (MEG) responses to continuous narrative speech, presented either as a single talker in a quiet background or as a two-talker mixture of a male and a female speaker. In clean speech, voice pitch was associated with a right-dominant response, peaking at a latency of around 100 ms, consistent with previous electroencephalography and electrocorticography results. The response tracked both the presence of pitch and the relative value of the speaker’s fundamental frequency. In the two-talker mixture, the pitch of the attended speaker was tracked bilaterally, regardless of whether or not there was simultaneously present pitch in the speech of the irrelevant speaker. Pitch tracking for the irrelevant speaker was reduced: only the right hemisphere still significantly tracked pitch of the unattended speaker, and only during intervals in which no pitch was present in the attended talker’s speech. Taken together, these results suggest that pitch-based segregation of multiple speakers, at least as measured by macroscopic cortical tracking, is not entirely automatic but strongly dependent on selective attention.
Chronic stability of activated iridium oxide film voltage transients from wireless floating microelectrode arrays
Authors: Frederick Rebecca A. , Shih Ellen , Towle Vernon L. , Joshi-Imre Alexandra , Troyk Philip R. , Cogan Stuart F.
Published: August 2022

Successful monitoring of the condition of stimulation electrodes is critical for maintaining chronic device performance for neural stimulation. As part of pre-clinical safety testing in preparation for a visual prostheses clinical trial, we evaluated the stability of the implantable devices and stimulation electrodes using a combination of current pulsing in saline and in canine visual cortex. Specifically, in saline we monitored the stability and performance of 3000 μm2 geometric surface area activated iridium oxide film (AIROF) electrodes within a wireless floating microelectrode array (WFMA) by measuring the voltage transient (VT) response through reverse telemetry. Eight WFMAs were assessed in vitro for 24 days, where n = 4 were pulsed continuously at 80 μA (16 nC/phase) and n = 4 remained in solution with no applied stimulation. Subsequently, twelve different WFMAs were implanted in visual cortex in n = 3 canine subjects (4 WFMAs each). After a 2-week recovery period, half of the electrodes in each of the twelve devices were pulsed continuously for 24 h at either 20, 40, 63, or 80 μA (200 μs pulse width, 100 Hz). VTs were recorded to track changes in the electrodes at set time intervals in both the saline and in vivo study. The VT response of AIROF electrodes remained stable during pulsing in saline over 24 days. Electrode polarization and driving voltage changed by less than 200 mV on average. The AIROF electrodes also maintained consistent performance, overall, during 24 h of pulsing in vivo. Four of the in vivo WFMA devices showed a change in polarization, access voltage, or driving voltage over time. However, no VT recordings indicated electrode failure, and the same trend was typically seen in both pulsed and unpulsed electrodes within the same device. Overall, accelerated stimulation testing in saline and in vivo indicated that AIROF electrodes in the WFMA were able to consistently deliver up to 16 nC per pulse and would be suitable for chronic clinical use.
Selective blockade of rat brain T-type calcium channels provides insights on neurophysiological basis of arousal dependent resting state functional magnetic resonance imaging signals
Authors: Khalilzad Sharghi Vahid , Maltbie Eric A. , Pan Wen-Ju , Keilholz Shella D. , Gopinath Kaundinya S.
Published: August 2022

A number of studies point to slow (0.1–2 Hz) brain rhythms as the basis for the resting-state functional magnetic resonance imaging (rsfMRI) signal. Slow waves exist in the absence of stimulation, propagate across the cortex, and are strongly modulated by vigilance similar to large portions of the rsfMRI signal. However, it is not clear if slow rhythms serve as the basis of all neural activity reflected in rsfMRI signals, or just the vigilance-dependent components. The rsfMRI data exhibit quasi-periodic patterns (QPPs) that appear to increase in strength with decreasing vigilance and propagate across the brain similar to slow rhythms. These QPPs can complicate the estimation of functional connectivity (FC) via rsfMRI, either by existing as unmodeled signal or by inducing additional wide-spread correlation between voxel-time courses of functionally connected brain regions. In this study, we examined the relationship between cortical slow rhythms and the rsfMRI signal, using a well-established pharmacological model of slow wave suppression. Suppression of cortical slow rhythms led to significant reduction in the amplitude of QPPs but increased rsfMRI measures of intrinsic FC in rats. The results suggest that cortical slow rhythms serve as the basis of only the vigilance-dependent components (e.g., QPPs) of rsfMRI signals. Further attenuation of these non-specific signals enhances delineation of brain functional networks.
Superoxide dismutase 2 ameliorates mitochondrial dysfunction in skin fibroblasts of Leber’s hereditary optic neuropathy patients
Authors: Zhou Qingru , Yao Shun , Yang Mingzhu , Guo Qingge , Li Ya , Li Lei , Lei Bo
Published: August 2022

Background

In Leber’s hereditary optic neuropathy (LHON), mtDNA mutations mediate mitochondrial dysfunction and apoptosis of retinal ganglion cells. Mitochondrial superoxide dismutase 2 (SOD2) is a crucial antioxidase against reactive oxygen species (ROS). This study aims to investigate whether SOD2 could ameliorate mtDNA mutation mediated mitochondrial dysfunction in skin fibroblasts of LHON patients and explore the underlying mechanisms.

Methods

The skin of normal healthy subjects and severe LHON patients harboring m.11778G > A mutation was taken to prepare immortalized skin fibroblast cell lines (control-iFB and LHON-iFB). LHON-iFB cells were transfected with SOD2 plasmid or negative control plasmid, respectively. In addition, human neuroblastoma SH-SY5Y cells and human primary retinal pigmental epithelium (hRPE) cells were stimulated by H2O2 after gene transfection. The oxygen consumption rate (OCR) was measured with a Seahorse extracellular flux analyzer. The level of ATP production, mitochondrial membrane potential, ROS and malondialdehyde (MDA) were measured separately with the corresponding assay kits. The expression level of SOD2, inflammatory cytokines and p-IκBα/IκBα was evaluated by western-blot. Assessment of apoptosis was performed by TUNEL assay.

Results

LHON-iFB exhibited lower OCR, ATP production, mitochondrial membrane potential but higher level of ROS and MDA than control-iFB. Western-blot revealed a significantly increased expression of IL-6 and p-IκBα/IκBα in LHON-iFB. Compared with the negative control, SOD2 overexpression increased OCR, ATP production and elevated mitochondrial membrane potential, but impaired ROS and MDA production. Besides, western-blot demonstrated exogenous SOD2 reduced the protein level of IL-6 and p-IκBα/IκBα. TUNEL assays suggested SOD2 inhibited cells apoptosis. Analogously, in SH-SY5Y and hRPE cells, SOD2 overexpression increased ATP production and mitochondrial membrane potential, but decreased ROS, MDA levels and suppressed apoptosis.

Conclusion

SOD2 upregulation inhibited cells apoptosis through ameliorating mitochondrial dysfunction and reducing NF-κB associated inflammatory response. This study further support exogenous SOD2 may be a promising therapy for the treatment of LHON.
Walking exercise alters pedunculopontine nucleus connectivity in Parkinson’s disease in a dose-dependent manner
Authors: Cai Jiayue , Liu Aiping , Wang Yuheng , Tan Sun Nee , Chomiak Taylor , Burt Jacqueline , Camicioli Richard , Hu Bin , McKeown Martin J. , Ba Fang
Published: August 2022

Background

Gait disturbances are critical motor symptoms in Parkinson’s disease (PD). The mechanisms of gait impairment in PD are not entirely understood but likely involve changes in the Pedunculopontine Nucleus (PPN), a critical locomotion center, and its associated connections. Exercise is universally accepted as helpful in PD, but the extent and intensity of exercise required for plastic changes are unclear.

Methods

Twenty-seven PD subjects participated in a 3-month gait training intervention. Clinical assessments and resting-state functional magnetic resonance imaging were performed at baseline and 3 months after exercise. Functional connectivity of PPN was assessed by combining the methods of partial least squares, conditional dependence and partial correlation. In addition, paired t-tests were used to examine the effect of exercise on PPN functional connectivity and clinical measures, and Pearson’s correlation was used to assess the association between altered PPN functional connectivity and clinical measures.

Results

Exercise significantly improved Unified Parkinson’s Disease Rating Scale-III (UPDRS-III). A significant increase in right PPN functional connectivity was observed after exercise, which did not correlate with motor improvement. However, the decrease in left PPN functional connectivity significantly correlated with the improvement in UPDRS-III and was linearly related to both number of walks and the duration of walks. In addition, exercise induced a significant increase in the laterality of PPN connectivity strength, which correlated with motor improvement.

Conclusion

PPN functional connectivity is modifiable by walking exercise in both a dose-independent (right PPN and laterality of PPN connectivity strength) and dose-dependent (left PPN) manner. The PPN may contribute to pathological and compensatory processes in PD gait control. The observed gait improvement by walking exercise is most likely due to the reversal of the maladaptive compensatory mechanism. Altered PPN functional connectivity can be a marker for exercise-induced motor improvement in PD.
Alterations in the default mode network in rolandic epilepsy with mild spike-wave index in non-rapid eye movement sleep
Authors: Li Yihan , Wang Yingfan , Jiang Ping , Sun Jintao , Chen Qiqi , Wang Xiaoshan
Published: August 2022

Purpose

Rolandic epilepsy (RE) is one of the most common epilepsy syndromes during childhood. The aim of this study was to investigate the alterations in the default mode network (DMN) of RE patients whose spike-wave index (SWI) was within the 50–85% range during non-rapid eye movement (NREM) during sleep, as well as to detect early neuroimaging markers.

Methods

Resting-state data was recorded for each subject using magnetoencephalography (MEG). DMN-related brain regions were chosen as regions of interest. The spectral power and functional connectivity (FC) of the DMN were estimated through the use of minimum norm estimation (MNE) combined with Welch technique and corrected amplitude envelope correlation (AEC-c).

Results

The patient group included 20 patients with NREM phase 50% ≤ SWI < 85% (mild SWI group), and 18 typical RE patients (SWI < 50% group). At the regional level, the mild SWI group exhibited enhanced spectral power in the delta band of the bilateral posterial cingulate cortex and attenuated the spectral power in the alpha band of the bilateral posterial cingulate cortex. Enhanced spectral power in the bilateral precuneus (PCu) in the delta band and attenuated spectral power in the right lateral temporal cortex (LTC) in the alpha band were common across all RE patients. At the FC level, patients in the mild SWI group indicated increased AEC-c values between the bilateral posterial cingulate cortex in the delta band and between the left medial frontal cortex (MFC) and bilateral posterial cingulate cortex in the alpha band. Increased AEC-c values between the right PCu and left MFC in the delta band, and between the left PCu and right MFC in the theta band, were common across all RE patients. Moreover, the spectral power in the bilateral posterial cingulate cortex in the alpha band and the AEC-c value between the bilateral posterial cingulate cortex in the delta band demonstrated good discrimination ability.

Conclusion

The spectral power of the bilateral posterior cingulate cortex (PCC) in the alpha band and the AEC-c value between the bilateral PCC in the delta band may be promising indicators of early differentiation between mild SWI and typical RE.
High-order brain functional network for electroencephalography-based diagnosis of major depressive disorder
Authors: Zhao Feng , Pan Hongxin , Li Na , Chen Xiaobo , Zhang Haicheng , Mao Ning , Ren Yande
Published: August 2022

Brain functional network (BFN) based on electroencephalography (EEG) has been widely used to diagnose brain diseases, such as major depressive disorder (MDD). However, most existing BFNs only consider the correlation between two channels, ignoring the high-level interaction among multiple channels that contain more rich information for diagnosing brain diseases. In such a sense, the BFN is called low-order BFN (LO-BFN). In order to fully explore the high-level interactive information among multiple channels of the EEG signals, a scheme for constructing a high-order BFN (HO-BFN) based on the “correlation’s correlation” strategy is proposed in this paper. Specifically, the entire EEG time series is firstly divided into multiple epochs by sliding window. For each epoch, the short-term correlation between channels is calculated to construct a LO-BFN. The correlation time series of all channel pairs are formulated by these LO-BFNs obtained from all epochs to describe the dynamic change of short-term correlation along the time. To construct HO-BFN, we cluster all correlation time series to avoid the problems caused by high dimensionality, and the correlation of the average correlation time series from different clusters is calculated to reflect the high-order correlation among multiple channels. Experimental results demonstrate the efficiency of the proposed HO-BFN in MDD identification, and its integration with the LO-BFN can further improve the recognition rate.
Adult health and transition stage-specific rotenone-mediated Drosophila model of Parkinson’s disease: Impact on late-onset neurodegenerative disease models
Authors: Ayajuddin Mohamad , Phom Limamanen , Koza Zevelou , Modi Priyanka , Das Abhik , Chaurasia Rahul , Thepa Abuno , Jamir Nukshimenla , Neikha Kelevikho , Yenisetti Sarat Chandra
Published: August 2022

Parkinson’s disease (PD) affects almost 1% of the population worldwide over the age of 50 years. Exposure to environmental toxins like paraquat and rotenone is a risk factor for sporadic PD which constitutes 95% of total cases. Herbicide rotenone has been shown to cause Parkinsonian symptoms in multiple animal models. Drosophila is an excellent model organism for studying neurodegenerative diseases (NDD) including PD. The aging process is characterized by differential expression of genes during different life stages. Hence it is necessary to develop life-stage-matched animal models for late-onset human disease(s) such as PD. Such animal models are critical for understanding the pathophysiology of age-related disease progression and important to understand if a genotropic drug/nutraceutical can be effective during late stages. With this idea, we developed an adult life stage-specific (health and transition phase, during which late-onset NDDs such as PD sets in) rotenone-mediated Drosophila model of idiopathic PD. Drosophila is susceptible to rotenone in dose-time dependent manner. Rotenone-mediated fly model of sporadic PD exhibits mobility defects (independent of mortality), inhibited mitochondrial complex I activity, dopaminergic (DAergic) neuronal dysfunction (no loss of DAergic neuronal number; however, reduction in rate-limiting enzyme tyrosine hydroxylase (TH) synthesis), and alteration in levels of dopamine (DA) and its metabolites; 3,4-Dihydroxyphenylacetic acid (DOPAC) and Homovanilic acid (HVA) in brain-specific fashion. These PD-linked behaviors and brain-specific phenotypes denote the robustness of the present fly model of PD. This novel model will be of great help to decipher life stage-specific genetic targets of small molecule mediated DAergic neuroprotection; understanding of which is critical for formulating therapeutic strategies for PD.
Higher modified dietary inflammatory index is associated with increased risk of osteoporosis in US adults: Data from NHANES
Authors: Chen Yong , Chen Fu-hua , Chen Yi-qing , Zhang Qiu
Published: August 2022

Objective

The aim of this study was to study the relationship between modified dietary inflammatory index (MDII) score with osteoporosis (OP) in adult Americans.

Methods

Data were extracted from the United States National Health and Nutrition Examination Survey (NHANES) (2007–2008, 2009–2010, 2013–2014, and 2017–2018). In this cross-sectional study, 5,446 participants were included and analyzed. Potential dietary inflammatory was assessed by MDII score (24-h recall), a composite method computed according to the relationship between nutrients and systemic pro-inflammatory cytokine level, and was further classified into tertiles. Weighted multivariable logistic regression analysis was employed to examine the associations between OP and MDII scores.

Results

In weighted multivariable-adjusted logistic regression models, the highest tertile of MDII score was associated with an increased risk of OP [odds ratio (OR): 1.73, 95% confidence interval (95 CI%): 1.14–2.63]. In participants aged above 59 years, a higher MDII score showed a higher risk of OP (OR: 1.92; 95 CI%: 1.16–3.15). In the sex-stratified models, the results remained significant only among women (OR: 1.80; 95% CI: 1.02–3.17). In the menopausal status stratified model, after adjusting potential confounding variables, the association between the MDII score, either as a categorical (OR: 1.88; 95% CI: 1.07–3.13) or continuous variables (OR: 1.19; 95%CI: 1.02–1.38), and OP risk was significant among postmenopausal women.

Conclusion

Our study indicates that a higher MDII score (pro-inflammatory effect) is significantly associated with an increased risk of OP in US adults, especially among those postmenopausal women more than 60 years. This study further supports that those dietary changes have the potential to prevent OP.
Ameliorative effects of epigallocatechin-3-gallate nanoparticles on 2,4-dinitrochlorobenzene induced atopic dermatitis: A potential mechanism of inflammation-related necroptosis
Authors: Han Mengguo , Wang Xue , Wang Jian , Lang Dongcen , Xia Xiaohua , Jia Yongfang , Chen Ying
Published: August 2022

Atopic dermatitis (AD) is a common autoimmune and chronic inflammatory cutaneous disease with a relapsing-remitting course. Necroptosis is a regulated necrotic cell death mediated by receptor-interacting protein 1 (RIP1), receptor-interacting protein 3 (RIP3), and mixed lineage kinase domain-like pseudokinase (MLKL), which is activated by tumor necrosis factor-α (TNF-α). However, the mechanism and the role of necroptosis have not been delineated in AD progression. (-)-Epigallocatechin-3-gallate (EGCG), the main biological activity of tea catechin, is well known for its beneficial effects in the treatment of skin diseases. Here, PEG-PLGA-EGCG nanoparticles (EGCG-NPs) were formulated to investigate the bioavailability of EGCG to rescue cellular injury following the inhibition of necroptosis after AD. 2,4-dinitrochlorobenzene (DNCB) was used to establish AD mouse models. As expected, topically applied EGCG-NPs elicited a significant amelioration of AD symptoms in skin lesions, including reductions in the ear and skin thickness, dermatitis score, and scratching behavior, which was accompanied by redox homeostasis restored early in the experiment. In addition, EGCG-NPs significantly decreased the expression of inflammatory cytokines like TNF-α, interferon-γ (IFN-γ), interleukin-4 (IL-4), interleukin-6 (IL-6), and interleukin-17A (IL-17A) in a time-dependent manner than those of in AD group. As a result, the overexpression of RIP1, RIP3, and MLKL in the entire epidermis layers was dramatically blocked by EGCG-NPs, as well as the expression ofphosphorylated p38 (p-p38), extracellular signal-regulated kinase 1 (ERK1), and extracellular signal-regulated kinase 2 (ERK2). These findings promote that EGCG-NPs formulation represents a promising drug-delivery strategy for the treatment of AD by maintaining the balance of Th1/Th2 inflammation response and targeting necroptosis.
Hypertension of liver-yang hyperactivity syndrome induced by a high salt diet by altering components of the gut microbiota associated with the glutamate/GABA-glutamine cycle
Authors: Zheng Tao , Wu Yi , Peng Mai-jiao , Xiao Nen-qun , Tan Zhou-jin , Yang Tao
Published: August 2022

The gut microbiota and metabolites are closely related to hypertension; however, the changes in the composition of the gut microbiome and metabolites linking a high salt diet to elevated blood pressure are not established. In this study, traditional Chinese medicine (TCM) syndrome of hypertension caused by high salt had been diagnosed and the pathogenesis of hypertension was explored from the perspective of intestinal microecology. Rats in a high salt diet-induced hypertension group (CG) and normal group (CZ) were compared by 16S rRNA gene full-length sequencing and liquid chromatography and mass spectrometry to identify differences in the bacterial community structure, metabolites, and metabolic pathways. Hypertension induced by a high salt diet belongs to liver-Yang hyperactivity syndrome. Alpha and beta diversity as well as the composition of microbiota from the phylum to species levels differed substantially between the CG and CZ groups. In an analysis of differential metabolites in the intestines, a high salt diet mainly affected the metabolism of amino acids and their derivatives; in particular, γ-aminobutyric acid (GABA) was down-regulated and glutamic acid and its derivatives were up-regulated under a high salt diet. Based on a KEGG analysis, high salt intake mainly altered pathways related to GABA and the glutamate/glutamine metabolism, such as the GABAergic synapse pathway and glutamatergic synapse pathway. The correlation analysis of differential gut microbes and differential metabolites suggested that a high salt diet promoted hypertension via the inhibition of Clostridiaceae_1 growth and alterations in the GABA metabolic pathway, leading to increased blood pressure. These findings suggest that a high salt diet induces hypertension of liver-Yang hyperactivity syndrome by mediating the microbiota associated with the glutamate/GABA-glutamine metabolic cycle via the gut–brain axis.
Maintenance therapy for AML after allogeneic HCT
Authors: Nayak Rahul K. , Chen Yi-Bin
Published: August 2022

Allogeneic hematopoietic cell transplant (allo-HCT) for eligible patients with acute myeloid leukemia (AML) in first complete remission is a central treatment paradigm to achieve durable remission. However, disease relapse after allo-HCT remains a significant concern and generally portends a poor prognosis. There is significant interest regarding the role for maintenance therapy after allo-HCT for patients with high risk of relapse, regardless of the presence of measurable residual disease. While there are currently no therapies approved for maintenance therapy for AML after allo-HCT, there are a number of ongoing investigations examining the role of maintenance therapies that include targeted agents against FLT3-ITD or IDH mutations, hypomethylating agents, immunomodulatory therapies and cellular therapies. In this review, we examine the current landscape and future strategies for maintenance therapy for AML after allo-HCT.
Growth hormone associated with treatment efficacy of immune checkpoint inhibitors in gastric cancer patients
Authors: Zhao Yue , Ji Zhengzheng , Li Jiasong , Zhang Shasha , Wu Chensi , Zhang Ruixing , Guo Zhanjun
Published: August 2022

Background

Immune checkpoint inhibitors (ICIs) combined with chemotherapy have been widely employed to improve the outcome of gastric cancer patients. In the present study, the impact of posttreatment growth hormone (GH) levels on the treatment efficacy of ICIs for advanced gastric cancer (AGC) patients was assessed.

Methods

Seventy-five AGC patients treated with anti-PD-1 antibodies at The Fourth Hospital of Hebei Medical University were involved. We divided AGC patients into two groups as high-GH group and low-GH group based on the GH level. Immunotherapy efficacy was assessed in terms of objective response rate, disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) based on the National Comprehensive Cancer Network Guidelines. The enumeration data were compared by χ2 test or Fisher’s exact test. Survival curves were drawn by the Kaplan–Meier method, and comparisons between the curves were made using the log-rank test. Multivariate survival analysis was performed using a Cox proportional hazards model.

Results

The higher GH levels were associated with a lower DCR of ICIs with a DCR of 30.0% in the high-GH group and 53.3% in the low-GH group (P = 0.046). The subsequent univariate analysis showed that a high GH level was associated with both shorter PFS (P = 0.016) and shorter OS at the borderline statistical level (P = 0.052) in AGC patients treated with ICIs. Cox model analysis also proved that the GH level was an independent risk factor for the outcome of AGC patients (PFS: P = 0.013, HR, 2.424, 95% CI, 1.202–4.890; OS: P = 0.014, HR, 3.301, 95% CI, 1.279–8.519).

Conclusions

The post-treatment GH level might be a predictor for ICIs treatment in AGC patients.
Machine-learning-based contrast-enhanced computed tomography radiomic analysis for categorization of ovarian tumors
Authors: Li Jiaojiao , Zhang Tianzhu , Ma Juanwei , Zhang Ningnannan , Zhang Zhang , Ye Zhaoxiang
Published: August 2022

Objectives

This study aims to evaluate the diagnostic performance of machine-learning-based contrast-enhanced CT radiomic analysis for categorizing benign and malignant ovarian tumors.

Methods

A total of 1,329 patients with ovarian tumors were randomly divided into a training cohort (N=930) and a validation cohort (N=399). All tumors were resected, and pathological findings were confirmed. Radiomic features were extracted from the portal venous phase images of contrast-enhanced CT. The clinical predictors included age, CA-125, HE-4, ascites, and margin of tumor. Both radiomics model (including selected radiomic features) and mixed model (incorporating selected radiomic features and clinical predictors) were constructed respectively. Six classifiers [k-nearest neighbor (KNN), support vector machines (SVM), random forest (RF), logistic regression (LR), multi-layer perceptron (MLP), and eXtreme Gradient Boosting (XGBoost)] were used for each model. The mean relative standard deviation (RSD) and area under the receiver operating characteristic curve (AUC) were applied to evaluate and select the best classifiers. Then, the performances of the two models with selected classifiers were assessed in the validation cohort.

Results

The MLP classifier with the least RSD (1.21 and 0.53, respectively) was selected as the best classifier in both radiomics and mixed models. The two models with MLP classifier performed well in the validation cohort, with the AUCs of 0.91 and 0.96 and with accuracies (ACCs) of 0.83 and 0.87, respectively. The Delong test showed that the AUC of mixed model was statistically different from that of radiomics model (p<0.001).

Conclusions

Machine-learning-based CT radiomic analysis could categorize ovarian tumors with good performance preoperatively. The mixed model with MLP classifier may be a potential tool in clinical applications.
Association of miR-181c/d gene locus rs8108402 C/T polymorphism with susceptibility to Kawasaki disease in Chinese children
Authors: Yao Meiqing , He Qin , Yang Manqiong , Wu Zhixiang , Li Ying , Kong Min , Kang Zhijuan , Yi Lu , Hu Yanan , Huang Lihua , Li Zhuoying , Yang Zuocheng
Published: August 2022

Background

Kawasaki disease (KD) is an acute systemic vasculitis of unknown etiology. The rs8108402 C/T single nucleotide polymorphism (SNP) is located in the promoter region of miR-181-c/d gene and the intron of Nanos3 gene. The miR-181 family contributes to the pathogenesis of cardiovascular and inflammatory disorders, while Nanos3 is involved in DNA transcription regulation and cell proliferation. However, no studies have examined the association between miR-181c/d and Nanos3 polymorphisms and the susceptibility and progression of KD.

Objective

The purpose of our study is to examine the association of miR-181c/miR-181d/Nanos3 gene locus rs8108402 C/T polymorphism with KD susceptibility, intravenous immunoglobulin (IVIG) responsiveness, and the development of coronary artery lesions (CAL).

Methods

Peripheral blood specimens from 100 children with KD and 100 healthy children were collected. The polymorphism of rs8108402 C/T was detected using polymerase chain reaction-sequencing-based typing technique.

Results

There were statistically significant differences in C and T allele frequency distributions between the KD group and healthy controls for the polymorphic site rs8108402 C/T (P = 0.002). The distribution of the genotypes CC, CT, and TT also presented statistical significant difference between the KD and control groups (P = 0.003). Compared to the rs8108402 C allele, the T allele was associated with increased KD susceptibility (OR = 2.080, 95% CI = 1.317∼3.283). However, there were no significant associations discovered between the rs8108402 C/T polymorphism and CAL formation or IVIG unresponsiveness in the study.

Conclusion

SNP rs8108402 C/T located in the miR-181c/d promoter and Nanos3 intronic region is associated with susceptibility to Kawasaki disease but not with the development of coronary artery lesions or IVIG unresponsiveness in Chinese children.
Morbidity and mortality in small for gestational age very preterm infants in a middle-income country
Authors: Mangiza Marcia , Ehret Danielle E. Y. , Edwards Erika M. , Rhoda Natasha , Tooke Lloyd
Published: August 2022

Objective

To evaluate the impact of small for gestational age (SGA) on outcomes of very preterm infants at Groote Schuur Hospital (GSH), Cape Town, South Africa.

Study design

Data were obtained from the Vermont Oxford Network (VON) GSH database from 2012 to 2018. The study is a secondary analysis of prospectively collected observational data. Fenton growth charts were used to define SGA as birth weight < 10th centile for gestational age.

Results

Mortality [28.9% vs. 18.5%, adjusted risk ratio (aRR) 2.1, 95% confidence interval (CI) 1.6–2.7], bronchopulmonary dysplasia (BPD; 14% vs. 4.5%, aRR 3.7, 95% CI 2.3–6.1), and late-onset sepsis (LOS; 16.7% vs. 9.6%, aRR 2.3, 95% CI 1.6–3.3) were higher in the SGA than in the non-SGA group.

Conclusion

Small for gestational age infants have a higher risk of mortality and morbidity among very preterm infants at GSH. This may be useful for counseling and perinatal management.
A Description of Acute Renal Failure and Nephrolithiasis Associated With Sodium–Glucose Co-Transporter 2 Inhibitor Use: A VigiBase Study
Authors: Frent Ioana , Leucuta Daniel , Bucsa Camelia , Farcas Andreea , Casoinic Florin , Mogosan Cristina
Published: August 2022

Background: The Food and Drug Administration issued a warning on the risk of acute kidney injury and a signal of nephrolithiasis for patients using sodium–glucose co-transporter 2 inhibitors (SGLT2i). We performed a descriptive analysis on acute renal failure (ARF) and nephrolithiasis cases reported to SGLT2i in the VigiBase®, in the scope of characterizing the patients and reactions and to report on the disproportionality analysis.

Methods: We analyzed all ARF and nephrolithiasis reports for SGLT2i in VigiBase from inception to September 2021. ARF cases were defined as reports containing at least one of the preferred terms (PTs) included in the ARF narrow Medical Dictionary for Regulatory Activities Standardised Queries (MedDRA SMQ). SGLT2i exposure was considered for reports with at least one gliflozin as a suspected/interacting drug. We characterized the patients, reporters, and reactions, and we present the proportional reporting ratio (PRR).

Results: Of 27,370,413 total reports in VigiBase, we found 3,972 ARF reactions to gliflozins as suspected/interacting drugs in 3,751 patients and 231 nephrolithiasis reactions in 227 patients. Most cases were reported from American regions (3057; 81.49%), for patients of age group 45–64 years (1590; 59%). About 30% (1156) of the ARF reports were registered in 2018, most from spontaneous reporting, and from consumers followed by healthcare professionals (2,235; 61% and 1440; 38%, respectively). Canagliflozin was the most involved gliflozin in the ARF and nephrolithiasis cases (2,640; 67% and 109; 47%, respectively). The great majority of ARF and nephrolithiasis reports were serious (3,761; 95% and 182; 79%, respectively). Of the total ARF cases reported, 51 had fatal outcome, while 152 had not recovered/not resolved outcome. No fatal outcome was reported for nephrolithiasis. Disproportionality analysis in full database showed a PRR of 4.68 (95% CI 4.53–4.83) for all gliflozins–ARF and a PRR of 3.44 (95% CI 3.00–3.95) for all gliflozins–nephrolithiasis.

Conclusion: Most of ARF reports associated with gliflozins were serious, with an important number of cases with fatal outcome. A drug safety signal was found between ARF narrow SMQ and gliflozins. Also, gliflozins were associated with an increase in the proportion of nephrolithiasis reports compared to other medications.
New insight into ischemic stroke: Circadian rhythm in post-stroke angiogenesis
Authors: Zhang Yuxing , Liu Lijuan , Zhao Xin , Yan Siyang , Zeng Fukang , Zhou Desheng
Published: August 2022

The circadian rhythm is an endogenous clock system that coordinates and optimizes various physiological and pathophysiological processes, which accord with the master and the peripheral clock. Increasing evidence indicates that endogenous circadian rhythm disruption is involved in the lesion volume and recovery of ischemic stroke. As a critical recovery mechanism in post-stroke, angiogenesis reestablishes the regional blood supply and enhances cognitive and behavioral abilities, which is mainly composed of the following processes: endothelial cell proliferation, migration, and pericyte recruitment. The available evidence revealed that the circadian governs many aspects of angiogenesis. This study reviews the mechanism by which circadian rhythms regulate the process of angiogenesis and its contribution to functional recovery in post-stroke at the aspects of the molecular level. A comprehensive understanding of the circadian clock regulating angiogenesis in post-stroke is expected to develop new strategies for the treatment of cerebral infarction.
AMTDB: A comprehensive database of autophagic modulators for anti-tumor drug discovery
Authors: Fu Jiahui , Wu Lifeng , Hu Gaoyong , Shi Qiqi , Wang Ruodi , Zhu Lingjuan , Yu Haiyang , Fu Leilei
Published: August 2022

Autophagy, originally described as a mechanism for intracellular waste disposal and recovery, has been becoming a crucial biological process closely related to many types of human tumors, including breast cancer, osteosarcoma, glioma, etc., suggesting that intervention of autophagy is a promising therapeutic strategy for cancer drug development. Therefore, a high-quality database is crucial for unraveling the complicated relationship between autophagy and human cancers, elucidating the crosstalk between the key autophagic pathways, and autophagic modulators with their remarkable antitumor activities. To achieve this goal, a comprehensive database of autophagic modulators (AMTDB) was developed. AMTDB focuses on 153 cancer types, 1,153 autophagic regulators, 860 targets, and 2,046 mechanisms/signaling pathways. In addition, a variety of classification methods, advanced retrieval, and target prediction functions are provided exclusively to cater to the different demands of users. Collectively, AMTDB is expected to serve as a powerful online resource to provide a new clue for the discovery of more candidate cancer drugs.
LC–MS-based lipidomic analysis of liver tissue sample from spontaneously hypertensive rats treated with extract hawthorn fruits
Authors: Sun Luping , Chi Bingqing , Xia Mingfeng , Ma Zhen , Zhang Hongbin , Jiang Haiqiang , Zhang Fang , Tian Zhenhua
Published: August 2022

At present, many experiments provide support for the cardiovascular protective effect of hawthorn (Crataegus oxyacantha) flower, leaf and fruit extracts. The aim of this study was to investigate the intervention mechanism of hawthorn fruit extract on spontaneously hypertensive rats (SHR) and its effect on their lipid metabolic pattern. After SHR was intervened by hawthorn extract (1.08 g/kg/d) for 6 weeks, the blood pressure and liver histopathology of rats were evaluated. An UHPLC-Q Extractive metabolomics approach was used to collect information on rat liver lipid metabolites, combined with multivariate data analysis to identify significantly different substances and potential biomarkers through mass spectrometry and database searches. Histomorphology of the liver was partially restored in the hawthorn-treated group. Hawthorn extract interferes with sphingolipid metabolism, glycerophospholipid metabolism and glycerolipids metabolism, improving partially disturbed metabolic pathways. This study showed that hawthorn could partially restore liver histomorphology and has anti-hypertensive effect by regulating lipid metabolism.