bluuebunny/crossref_metadata_2025 huggingface dataset:
Deducing the Impact of Physical Activity, Sedentary Behavior, and Physical Performance on Cognitive Function in Healthy Older Adults
Authors: Gerten Sina , Engeroff Tobias , Fleckenstein Johannes , Füzéki Eszter , Matura Silke , Pilatus Ulrich , Vogt Lutz , Pantel Johannes , Banzer Winfried
Published: January 2022

Objectives: Participating in physical activity and maintaining physical performance as well as reducing sedentary behavior are discussed to be beneficially associated with cognitive function in older adults. The purpose of this cross-sectional analysis was to differentiate the relevance of objectively measured physical activity, physical performance, and sedentary behavior on cognitive function in healthy older adults (n = 56, age = 76 ± 7 yrs, gender = 30 female).

Methods: Accelerometer based physical activity and sedentary behavior were analyzed as minutes per week spent sedentary and physically active with light or moderate to vigorous intensity. Participants' physical performance was assessed via cardiopulmonary exercise testing and analyzed as maximal workload and heart rate, heart rate reserve and peak oxygen uptake. The assessment of cognitive function included working memory, attention, executive function, and verbal memory. Data was analyzed with Spearman and partial correlations. Trial registration: NCT02343029.

Results: Light physical activity was moderately associated with executive function (r = −0.339, p = 0.015). Attention was significantly associated with maximal workload (r = −0.286, p = 0.042) and peak oxygen uptake (r = −0.337, p = 0.015). Working memory was associated with maximal workload (r = 0.329, p = 0.017).

Conclusion: Whereas a broad range of cognitive function were beneficially linked to physical performance, light intensity activities in particular showed an impact on executive function. Our research underlines the need to separate the impact of physical performance and physical activity on cognitive function and highlights the relevance of light physical activity.
Glial Patchwork: Oligodendrocyte Progenitor Cells and Astrocytes Blanket the Central Nervous System
Authors: Barber Heather M. , Ali Maria F. , Kucenas Sarah
Published: January 2022

Tiling is a developmental process where cell populations become evenly distributed throughout a tissue. In this review, we discuss the developmental cellular tiling behaviors of the two major glial populations in the central nervous system (CNS)—oligodendrocyte progenitor cells (OPCs) and astrocytes. First, we discuss OPC tiling in the spinal cord, which is comprised of the three cellular behaviors of migration, proliferation, and contact-mediated repulsion (CMR). These cellular behaviors occur simultaneously during OPC development and converge to produce the emergent behavior of tiling which results in OPCs being evenly dispersed and occupying non-overlapping domains throughout the CNS. We next discuss astrocyte tiling in the cortex and hippocampus, where astrocytes migrate, proliferate, then ultimately determine their exclusive domains by gradual removal of overlap rather than sustained CMR. This results in domains that slightly overlap, allowing for both exclusive control of “synaptic islands” and astrocyte-astrocyte communication. We finally discuss the similarities and differences in the tiling behaviors of these glial populations and what remains unknown regarding glial tiling and how perturbations to this process may impact injury and disease.
Glial Purinergic Signals and Psychiatric Disorders
Authors: Koizumi Schuichi
Published: January 2022

Emotion-related neural networks are regulated in part by the activity of glial cells, and glial dysfunction can be directly related to emotional diseases such as depression. Here, we discuss three different therapeutic strategies involving astrocytes that are effective for treating depression. First, the antidepressant, fluoxetine, acts on astrocytes and increases exocytosis of ATP. This has therapeutic effects via brain-derived neurotrophic factor-dependent mechanisms. Second, electroconvulsive therapy is a well-known treatment for drug-resistant depression. Electroconvulsive therapy releases ATP from astrocytes to induce leukemia inhibitory factors and fibroblast growth factor 2, which leads to antidepressive actions. Finally, sleep deprivation therapy is well-known to cause antidepressive effects. Sleep deprivation also increases release of ATP, whose metabolite, adenosine, has antidepressive effects. These independent treatments share the same mechanism, i.e., ATP release from astrocytes, indicating an essential role of glial purinergic signals in the pathogenesis of depression.
A Preoperative MRI-Based Radiomics-Clinicopathological Classifier to Predict the Recurrence of Pituitary Macroadenoma Within 5 Years
Authors: Zhang Yu , Luo Yuqi , Kong Xin , Wan Tao , Long Yunling , Ma Jun
Published: January 2022

Objective: To investigate the ability of a MRI-based radiomics-clinicopathological model to predict pituitary macroadenoma (PMA) recurrence within 5 years.

Materials and Methods: We recruited 74 recurrent and 94 non-recurrent subjects, following first surgery with 5-year follow-up data. Univariate and multivariate analyses were conducted to identify independent clinicopathological risk factors. Two independent and blinded neuroradiologists used 3D-Slicer software to manually delineate whole tumors using preoperative axial contrast-enhanced T1WI (CE-T1WI) images. 3D-Slicer was then used to extract radiomics features from segmented tumors. Dimensionality reduction was carried out by the least absolute shrinkage and selection operator (LASSO). Two multilayer perceptron (MLP) models were established, including independent clinicopathological risk factors (Model 1) and a combination of screened radiomics features and independent clinicopathological markers (Model 2). The predictive performance of these models was evaluated by receiver operator characteristic (ROC) curve analysis.

Results: In total, 1,130 features were identified, and 4 of these were selected by LASSO. In the test set, the area under the curve (AUC) of Model 2 was superior to Model 1 {0.783, [95% confidence interval (CI): 0.718—.860] vs. 0.739, (95% CI: 0.665–0.818)}. Model 2 also yielded the higher accuracy (0.808 vs. 0.692), sensitivity (0.826 vs. 0.652), and specificity (0.793 vs. 0.724) than Model 1.

Conclusions: The integrated classifier was superior to a clinical classifier and may facilitate the prediction of individualized prognosis and therapy.
Iron Deposition in Gray Matter Nuclei of Patients With Intracranial Artery Stenosis: A Quantitative Susceptibility Mapping Study
Authors: Mao Huimin , Dou Weiqiang , Wang Xinyi , Chen Kunjian , Wang Xinyu , Guo Yu , Zhang Chao
Published: January 2022

Purpose: This study aimed to use quantitative susceptibility mapping (QSM) to systematically investigate the changes of iron content in gray matter (GM) nuclei in patients with long-term anterior circulation artery stenosis (ACAS) and posterior circulation artery stenosis (PCAS).

Methods: Twenty-five ACAS patients, 25 PCAS patients, and 25 age- and sex-matched healthy controls underwent QSM examination. Patients were scored using the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) to assess the degree of neural function deficiency. On QSM images, iron related susceptibility of GM nuclei, including bilateral caudate nucleus, putamen (PU), globus pallidus (GP), thalamus (TH), substantia nigra (SN), red nucleus, and dentate nucleus (DN), were assessed. Susceptibility was compared between bilateral GM nuclei in healthy controls, ACAS patients, and PCAS patients. Partial correlation analysis, with age as a covariate, was separately performed to assess the relationships of susceptibility with NIHSS and mRS scores.

Results: There were no significant differences between the susceptibilities for left and right hemispheres in all seven GM nucleus subregions for healthy controls, ACAS patients, and PCAS patients. Compared with healthy controls, mean susceptibility of bilateral PU, GP, and SN in ACAS patients and of bilateral PU, GP, SN, and DN in PCAS patients were significantly increased (all P < 0.05). In addition, mean susceptibility of bilateral TH and SN in PCAS patients was significantly higher than in ACAS patients (both P < 0.05). With partial correlation analysis, mean susceptibility at bilateral PU of ACAS patients was significantly correlated with mRS score (r = 0.415, P < 0.05), and at bilateral PU in PCAS patients was correlated with NIHSS score (r = 0.424, P < 0.05).

Conclusion: Our findings indicated that abnormal iron metabolism may present in different subregions of GM nuclei after long-term ACAS and PCAS. In addition, iron content of PU in patients with ACAS and PCAS was correlated with neurological deficit scores. Therefore, iron quantification measured by QSM susceptibility may provide a new insight to understand the pathological mechanism of ischemic stroke caused by ACAS and PCAS.
A New Coordinate System for Magnetic Resonance Imaging of the Vestibular System
Authors: Liu Weixing , Chen Gui , Xie Junyang , Liang Tianhao , Zhang Chunyi , Liao Xiao , Liao Wenjing , Song Lijuan , Zhang Xiaowen
Published: January 2022

Objectives: To develop and evaluate a new coordinate system for MRI of the vestibular system.

Methods: In this study, 53 internal auditory canal MRI and 78 temporal bone CT datasets were analyzed. Mimics Medical software version 21.0 was used to visualize and three-dimensionally reconstruct the image data. We established a new coordinate system, named W–X, based on the center of the bilateral eyeballs and vertex of the bilateral superior semicircular canals. Using the W–X coordinate system and Reid's coordinate system, we measured the orientations of the planes of the anterior semicircular canal (ASCC), the lateral semicircular canal (LSCC), and the posterior semicircular canal (PSCC).

Results: No significant differences between the angles measured using CT and MRI were found for any of the semicircular canal planes (p > 0.05). No statistical differences were found between the angles measured using Reid's coordinate system (CT) and the W–X coordinate system (MRI). The mean values of ∠ASCC & LSCC, ∠ASCC & PSCC, and ∠LSCC & PSCC were 84.67 ± 5.76, 94.21 ± 3.81, and 91.79 ± 5.22 degrees, respectively. The angle between the LSCC plane and the horizontal imaging plane was 15.64 ± 3.92 degrees, and the angle between the PSCC plane and the sagittal imaging plane was 48.79 ± 4.46 degrees.

Conclusion: A new W–X coordinate system was developed for MRI studies of the vestibular system and can be used to measure the orientations of the semicircular canals.
Adenosinergic Signaling as a Key Modulator of the Glioma Microenvironment and Reactive Astrocytes
Authors: Debom Gabriela N. , Rubenich Dominique S. , Braganhol Elizandra
Published: January 2022

Astrocytes are numerous glial cells of the central nervous system (CNS) and play important roles in brain homeostasis. These cells can directly communicate with neurons by releasing gliotransmitters, such as adenosine triphosphate (ATP) and glutamate, into the multipartite synapse. Moreover, astrocytes respond to tissue injury in the CNS environment. Recently, astrocytic heterogeneity and plasticity have been discussed by several authors, with studies proposing a spectrum of astrocytic activation characterized by A1/neurotoxic and A2/neuroprotective polarization extremes. The fundamental roles of astrocytes in communicating with other cells and sustaining homeostasis are regulated by purinergic signaling. In the CNS environment, the gliotransmitter ATP acts cooperatively with other glial signaling molecules, such as cytokines, which may impact CNS functions by facilitating/inhibiting neurotransmitter release. Adenosine (ADO), the main product of extracellular ATP metabolism, is an important homeostatic modulator and acts as a neuromodulator in synaptic transmission via P1 receptor sensitization. Furthermore, purinergic signaling is a key factor in the tumor microenvironment (TME), as damaged cells release ATP, leading to ADO accumulation in the TME through the ectonucleotidase cascade. Indeed, the enzyme CD73, which converts AMP to ADO, is overexpressed in glioblastoma cells; this upregulation is associated with tumor aggressiveness. Because of the crucial activity of CD73 in these cells, extracellular ADO accumulation in the TME contributes to sustaining glioblastoma immune escape while promoting A2-like activation. The present review describes the importance of ADO in modulating astrocyte polarization and simultaneously promoting tumor growth. We also discuss whether targeting of CD73 to block ADO production can be used as an alternative cancer therapy.
Transcriptomic Signatures Associated With Gray Matter Volume Changes in Patients With Functional Constipation
Authors: Cai Wangli , Zhou Yujing , Wan Lidi , Zhang Ruiling , Hua Ting , Gong Jian , Yang Bo , Tang Guangyu
Published: January 2022

Functional constipation, which belongs to the functional gastrointestinal disorder (FGID), is a common disease and significantly impacts daily life. FGID patients have been progressively proven with functional and structural alterations in various brain regions, but whether and how functional constipation affects the brain gray matter volume (GMV) remains unclear; besides, which genes are associated with the GMV changes in functional constipation is largely unknown. On account of the structural MRI image from the 30 functional constipation patients and 30 healthy controls (HCs), GMV analysis showed that functional constipation patients had significantly decreased GMV in the right orbital prefrontal cortex (OFC), left precentral gyrus (PreG), and bilateral thalamus (THA). Correlation analysis showed that the self-rating depressive scale, patient assessment of constipation quality of life (PAC-QOL), and Wexner constipation scores were negatively correlated with GMV of the OFC and negative correlations between PAC-QOL score and GMV of the bilateral THA. Based on the Allen Human Brain Atlas, a cross-sample spatial correlation was conducted and found that 18 genes’ expression values showed robust correlations with GMV changes in functional constipation patients. These outcomes highlight our recognition of the transcriptional features related to GMV changes in functional constipation and could be regarded as candidates to detect biological mechanisms of abnormality in functional constipation patients.
Interaction of Gut Microbiota and Brain Function in Patients With Chronic Insomnia: A Regional Homogeneity Study
Authors: Feng Ying , Fu Shishun , Li Cheng , Ma Xiaofen , Wu Yunfan , Chen Feng , Li Guomin , Liu Mengchen , Liu Hang , Zhu Jiaying , Lan Zhihong , Jiang Guihua
Published: January 2022

Recent studies have shown that the human gut microbiota (GM) plays a critical role in brain function and behavior via the complex microbiome–gut–brain axis. However, knowledge about the underlying relationship between the GM and changes in brain function in patients with chronic insomnia (CI) is still very limited. In this prospective study, 31 CI patients and 30 healthy controls were recruited. Resting-state functional magnetic resonance imaging scans were performed and brain functional alterations in CI patients were evaluated using the regional homogeneity (ReHo) method. We collected fecal samples of CI patients and used 16S rDNA amplicon sequencing to assess the relative abundance (RA) and alpha diversity of the GM. We also performed extensive sleep, mood, and cognitive assessments. Then, we tested for potential associations between the GM profile, ReHo alterations, and neuropsychological changes in CI patients. Our results showed associations between the RA of Lactobacilli, ReHo values in the left fusiform gyrus, and depression scores in CI patients. We also found some bacterial genera related to ReHo values of the right triangular inferior frontal gyrus. In addition, the RA of genus Coprobacter was correlated with ReHo values of the left angular gyrus and with specific cognitive performance. These findings revealed complex relationships between GM, brain function, and behavior in patients with CI.
High Internal-Phase Pickering Emulsions Stabilized by Xanthan Gum/Lysozyme Nanoparticles: Rheological and Microstructural Perspective
Authors: Xu Wei , Li Zhifan , Sun Haomin , Zheng Shuqing , Li He , Luo Denglin , Li Yingying , Wang Mengyuan , Wang Yuntao
Published: January 2022

Food-grade high internal-phase Pickering emulsions (HIPPEs) stabilized by solid or colloidal particles with different advantages have attracted extensive attention nowadays. However, looking for new appropriate particle stabilizers is the common practice for HIPPEs preparation. It is crucial to find a new strategy for the development of functional HIPPEs with controllable properties. In this study, a high concentration of xanthan gum/lysozyme nanoparticles (XG/Ly NPs) was used for the preparation of HIPPEs for the first time. Visual observations, creaming index (CI), microstructure, and rheology tests were carried out to investigate the potential of XG/Ly NPs as HIPPEs stabilizers. Results indicated that XG/Ly NPs could stabilize oil droplets in the concentration range of 0.5–4% (w/v). The HIPPEs with a minimal particle concentration of 1% exhibited remarkable physical stability. Rheological measurements showed that a high stability of solid-like HIPPEs was successfully obtained with a higher concentration of XG/Ly NPs. Overall, the HIPPEs stabilized by different concentrations of XG/Ly NPs exhibited excellent rheological and structural properties, which might provide a feasible strategy for the development of functional emulsion systems with controllable structures.
Intestinal Microbiota and Serum Metabolic Profile Responded to Two Nutritional Different Diets in Mice
Authors: Wu Zhifeng , Cheng Wei , Wang Zhenyu , Feng Shuaifei , Zou Huicong , Tan Xiang , Yang Yapeng , Wang Yuqing , Zhang Hang , Dong Miaomiao , Xiao Yingping , Tao Shiyu , Wei Hong
Published: January 2022

There is an interaction and bidirectional selection between dietary intake and gut microbiota due to the different efficiency of nutrients in the gut. The nutritional composition of germ-free (GF) diets differs significantly from specific pathogen-free (SPF) diets. There is, however, no data revealing how SPF animals from the same microbial background respond to them and if they affect the host. We examined the growth of SPF mice on the GF diet and found that it reduced body weight, intestinal length and intestinal morphology. Interestingly, the GF diet increased the level of pro-inflammatory bacteria in the gut of SPF mice, including Proteobacteria, Burkholderiaceae, Alloprevotella and Parasutterella. Furthermore, GF diets caused significant increases in malondialdehyde (MDA), IL-1β, IL-6, and D-lactate levels in the serum of SPF mice and significantly altered their serum metabolic profile, especially amino acid metabolism. In conclusion, GF diets are not suitable for the growth and development of SPF mice. These findings, based on the role of gut microbiota in diet selection, provide new insights into the scientific and rational use of experimental animal diets.
SARS-CoV-2 Transmission Dynamics in Households With Children, Los Angeles, California
Authors: Tanaka Melissa Lucero , Marentes Ruiz Carolyn Jennifer , Malhotra Sanchi , Turner Lauren , Peralta Ariana , Lee Yesun , Jumarang Jaycee , Perez Stephanie E. , Navarro Jocelyn , Dien Bard Jennifer , Gordon Aubree , Allen E. Kaitlynn , Thomas Paul G. , Pannaraj Pia S.
Published: January 2022

Objectives: Studies of household transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) focused on households with children are limited. We investigated household secondary attack rate (SAR), transmission dynamics, and contributing factors in households with children.

Materials and Methods: In this prospective case-ascertained study in Los Angeles County, California, all households members were enrolled if ≥1 member tested positive for SARS-CoV-2 by polymerase chain reaction (PCR). Nasopharyngeal PCRs, serology, and symptom data were obtained over multiple visits.

Results: A total of 489 individuals in 105 households were enrolled from June to December 2020. The majority (77.3%) reported a household annual income of <$50,000, and most (92.9%) were of Hispanic/Latinx ethnicity. Children <18 years old accounted for 46.9% index cases, of whom 45.3% were asymptomatic. Household index cases were predominantly children during low community transmission and adults during the high community transmission period (χ2 = 7.647, p = 0.0036. The mean household SAR was 77.0% (95% CI: 69.4–84.6%). Child and adult index cases both efficiently transmitted SARS-CoV-2 within households [81.9%, (95% CI: 72.1–91.9%) vs. 72.4% (95% CI: 59.8–85.1%), p = 0.23]. Household income and pets were significantly associated with higher SAR in the multivariable analysis of household factors (p = 0.0013 and 0.004, respectively).

Conclusions: The SAR in households with children in an urban setting with a large ethnic minority population is much higher than previously described. Children play important roles as index cases. SAR was disproportionately impacted by household income. Vaccination and public health efforts need special focus on children and vulnerable communities to help mitigate SARS-CoV-2 spread.
Resolvin D1 Attenuates Doxorubicin-Induced Cardiotoxicity by Inhibiting Inflammation, Oxidative and Endoplasmic Reticulum Stress
Authors: Wang Menglong , Zhang Jishou , Zhao Mengmeng , Liu Jianfang , Ye Jing , Xu Yao , Wang Zhen , Ye Di , Li Dan , Wan Jun
Published: January 2022

Resolvin D1 (RvD1) is a lipid mediator that promotes resolution of inflammation. However, the function of RvD1 in doxorubicin- (Dox-) induced cardiotoxicity remains to be clarified. This study aimed to investigate whether RvD1 could attenuate Dox-induced cardiac injury. The mice were divided into three groups: control, Dox (20 mg/kg, once, intraperitoneally), and Dox + RvD1. RvD1 (2.5 μg/kg, intraperitoneally) was injected daily for 5 days. Echocardiography was performed to evaluate the cardiac function, and the heart tissue and serum samples were collected for further analyses. The results showed that RvD1 attenuated the decreased ratio of heart weight/body weight and heart weight/tibia length, the increased level of creatine kinase and activity of lactate dehydrogenase after Dox treatment. RvD1 improved the ejection fraction and fractional shortening of left ventricular and attenuated the severity of apoptosis induced by Dox. As for the underlying pathways, the results showed that RvD1 reduced the expression of IL-1 and IL-6, and attenuated the phosphorylation of P65 in cardiac tissue. RvD1 attenuated the oxidative stress induced by Dox, as demonstrated by the attenuated levels of superoxide dismutase, glutathione, and malondialdehyde, decreased expression of Nox-2 and Nox-4 and increased expression of Nrf-2 and HO-1. In addition, RvD1 also inhibited the endoplasmic reticulum stress induced by Dox. These results indicate the potential therapeutic benefits of RvD1 in Dox-induced cardiotoxicity in mice, and the mechanism may be related to the attenuated inflammation, oxidative stress and endoplasmic reticulum stress.
A Non-Invasive Method for Detection of Antihypertensive Drugs in Biological Fluids: The Salivary Therapeutic Drug Monitoring
Authors: Avataneo Valeria , Fanelli Elvira , De Nicolò Amedeo , Rabbia Franco , Palermiti Alice , Pappaccogli Marco , Cusato Jessica , De Rosa Francesco Giuseppe , D'Avolio Antonio , Veglio Franco
Published: January 2022

Objectives: Arterial hypertension is still the most frequent cause of cardiovascular and cerebrovascular morbidity and mortality. Antihypertensive treatment has proved effective in reduction of cardiovascular risk. Nevertheless, lifestyle interventions and pharmacological therapy in some cases are ineffective in reaching blood pressure target values, despite full dose and poly-pharmacological treatment. Poor adherence to medications is an important cause of treatment failure. Different methods to assess therapeutic adherence are currently available: Therapeutic drug monitoring in biological fluids has previously demonstrated its efficacy and reliability. Plasma and urine have been already used for this purpose, but they may be affected by some practical limitations. Saliva may represent a feasible alternative.

Methods: Fourteen antihypertensive drugs and two metabolites were simultaneously tested in plasma, urine, and saliva. Tested molecules included: atenolol, nebivolol, clonidine, ramipril, olmesartan, telmisartan, valsartan, amlodipine, nifedipine, doxazosin, chlorthalidone, hydrochlorothiazide, indapamide, sacubitril, ramiprilat, and sacubitrilat. Therapeutic drug monitoring was performed using ultra-high performance liquid chromatography, coupled to tandem mass spectrometry (UHPLC-MS/MS). The method has been preliminarily evaluated in a cohort of hypertensive patients.

Results: The method has been validated according to US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines. The application on a cohort of 32 hypertensive patients has demonstrated sensibility and specificity of 98% and 98.1%, respectively, with a good feasibility in real-life clinical practice.

Conclusion: Saliva may represent a feasible biological sample for therapeutic drug monitoring by non-invasive collection, prompt availability, and potential accessibility also in out-of-clinic settings.
From AVATAR Mice to Patients: RC48-ADC Exerted Promising Efficacy in Advanced Gastric Cancer With HER2 Expression
Authors: Chen Zuhua , Yuan Jiajia , Xu Yingying , Zhang Cheng , Li Zhongwu , Gong Jifang , Li Yanyan , Shen Lin , Gao Jing
Published: January 2022

RC48-ADC is a novel humanized antibody specific for human epidermal growth factor receptor 2 (HER2)in conjugation with a microtubule inhibitor via a cleavable linker. This study was to evaluate the antitumor activity and mechanism of RC48-ADC in gastric cancer (GC) and explore the population that may benefit from RC48-ADC treatment. Four human GC cell lines and nine patient-derived xenograft (PDX) models were exploited to evaluate the antitumor effect of RC48-ADC or trastuzumab treatment in vitro and in vivo. The expression and phosphorylation of HER2 were assessed by immunohistochemistry (IHC) staining. Critical molecules of downstream PI3K/AKT and cell cycle and apoptosis signaling pathways were detected and quantified by immunoblotting. Combined with preliminary results of preclinical research, three patients with IHC3+, IHC2+/FISH+, and IHC2+/FISH- of HER2 were enrolled to verify the efficacy of RC48-ADC treatment in advanced GC. In vitro, RC48-ADC had superior antiproliferative effects in a dose-dependent manner on GC cells, especially on HER2-positive cells. In vivo, RC48-ADC exceeded trastuzumab in GC PDX models with HER2 expression, even in models with moderate to low expression of HER2. Further exploration of mechanism showed that RC48-ADC exerted the antitumor effect by inhibiting phosphorylation of HER2, inducing G2/M phase arrest and cell apoptosis in HER2-expressed PDX models. In clinical practice, RC48-ADC had satisfactory efficacy in HER2-positive and HER2 moderately expressed GC patients and demonstrated promising efficacy in HER2-positive patients who have progressed after anti-HER2 therapy. In conclusion, RC48-ADC exerted promising antitumor activity in HER2-positive as well as score of 2+ in IHC and ISH-negative AGC patients after progression of systematic treatment.
Natural Products Targeting Liver X Receptors or Farnesoid X Receptor
Authors: She Jianglian , Gu Tanwei , Pang Xiaoyan , Liu Yonghong , Tang Lan , Zhou Xuefeng
Published: January 2022

Nuclear receptors (NRs) are a superfamily of transcription factors induced by ligands and also function as integrators of hormonal and nutritional signals. Among NRs, the liver X receptors (LXRs) and farnesoid X receptor (FXR) have been of significance as targets for the treatment of metabolic syndrome-related diseases. In recent years, natural products targeting LXRs and FXR have received remarkable interests as a valuable source of novel ligands encompassing diverse chemical structures and bioactive properties. This review aims to survey natural products, originating from terrestrial plants and microorganisms, marine organisms, and marine-derived microorganisms, which could influence LXRs and FXR. In the recent two decades (2000–2020), 261 natural products were discovered from natural resources such as LXRs/FXR modulators, 109 agonists and 38 antagonists targeting LXRs, and 72 agonists and 55 antagonists targeting FXR. The docking evaluation of desired natural products targeted LXRs/FXR is finally discussed. This comprehensive overview will provide a reference for future study of novel LXRs and FXR agonists and antagonists to target human diseases, and attract an increasing number of professional scholars majoring in pharmacy and biology with more in-depth discussion.
Quercetin Attenuates Podocyte Apoptosis of Diabetic Nephropathy Through Targeting EGFR Signaling
Authors: Liu Yiqi , Li Yuan , Xu Liu , Shi Jiasen , Yu Xiujuan , Wang Xue , Li Xizhi , Jiang Hong , Yang Tingting , Yin Xiaoxing , Du Lei , Lu Qian
Published: January 2022

Podocytes injury is one of the leading causes of proteinuria in patients with diabetic nephropathy (DN), and is accompanied by podocytes apoptosis and the reduction of podocyte markers such as synaptopodin and nephrin. Therefore, attenuation of podocyte apoptosis is considered as an effective strategy to prevent the proteinuria in DN. In this study, we evaluated the anti-podocyte-apoptosis effect of quercetin which is a flavonol compound possessing an important role in prevention and treatment of DN and verified the effect by using db/db mice and high glucose (HG)-induced mouse podocytes (MPs). The results show that administration of quercetin attenuated the level of podocyte apoptosis by decreasing the expression of pro-apoptotic protein Bax, cleaved caspase 3 and increasing the expression of anti-apoptotic protein Bcl-2 in the db/db mice and HG-induced MPs. Furthermore, epidermal growth factor receptor (EGFR) was predicted to be the potential physiological target of quercetin by network pharmacology. In vitro and vivo experiments confirmed that quercetin inhibited activation of the EGFR signaling pathway by decreasing phosphorylation of EGFR and ERK1/2. Taken together, this study demonstrates that quercetin attenuated podocyte apoptosis through inhibiting EGFR signaling pathway, which provided a novel approach for further research of the mechanism of quercetin in the treatment of DN.
Insights on Cancer Cell Inhibition, Subcellular Activities, and Kinase Profile of Phenylacetamides Pending 1H-Imidazol-5-One Variants
Authors: Khayat Maan T. , Omar Abdelsattar M. , Ahmed Farid , Khan Mohammad I. , Ibrahim Sara M. , Muhammad Yosra A. , Malebari Azizah M. , Neamatallah Thikryat , El-Araby Moustafa E.
Published: January 2022

Structural changes of small-molecule drugs may bring interesting biological properties, especially in the field of kinase inhibitors. We sought to study tirbanibulin, a first-in-class dual Src kinase (non-ATP competitive)/tubulin inhibitor because there was not enough reporting about its structure–activity relationships (SARs). In particular, the present research is based on the replacement of the outer ring of the biphenyl system of 2-[(1,1′-biphenyl)-4-yl]-N-benzylacetamide, the identified pharmacophore of KX chemotype, with a heterocyclic ring. The newly synthesized compounds showed a range of activities in cell-based anticancer assays, agreeing with a clear SAR profile. The most potent compound, (Z)-N-benzyl-4-[4-(4-methoxybenzylidene)-2-methyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl]phenylacetamide (KIM-161), demonstrated cytotoxic IC50 values at 294 and 362 nM against HCT116 colon cancer and HL60 leukemia cell lines, respectively. Profiling of this compound (aqueous solubility, liver microsomal stability, cytochrome P450 inhibition, reactivity with reduced glutathione, and plasma protein binding) confirmed its adequate drug-like properties. Mechanistic studies revealed that this compound does not depend on tubulin or Src kinase inhibition as a factor in forcing HL60 to exit its cell cycle and undergo apoptosis. Instead, KIM-161 downregulated several other kinases such as members of BRK, FLT, and JAK families. It also strongly suppresses signals of ERK1/2, GSK-3α/β, HSP27, and STAT2, while it downregulated AMPKα1 phosphorylation within the HL60 cells. Collectively, these results suggest that phenylacetamide-1H-imidazol-5-one (KIM-161) could be a promising lead compound for further clinical anticancer drug development.
Pharmacotherapies for Drug-Induced Liver Injury: A Current Literature Review
Authors: Li Meng , Luo Qiong , Tao Yanyan , Sun Xin , Liu Chenghai
Published: January 2022

Drug-induced liver injury (DILI) has become a serious public health problem. For the management of DILI, discontinuation of suspicious drug or medicine is the first step, but the treatments including drugs and supporting approaches are needed. Reference to clinical patterns and disease severity grades of DILI, the treatment drugs were considered to summarize into hepatoprotective drugs (N-acetylcysteine and Glutathione, Glycyrrhizin acid preparation, Polyene phosphatidylcholine, Bicyclol, Silymarin), anticholestatic drug (Ursodeoxycholic acid, S-adenosylmethionine, Cholestyramine), immunosuppressants (Glucocorticoids) and specific treatment agents (L-carnitine, Anticoagulants). The current article reviewed the accumulated literature with evidence-based medicine researches for DILI in clinical practice. Also the drawbacks of the clinical studies involved in the article, unmet needs and prospective development for DILI therapy were discussed.
HetInf: Social Influence Prediction With Heterogeneous Graph Neural Network
Authors: Gao Liqun , Wang Haiyang , Zhang Zhouran , Zhuang Hongwu , Zhou Bin
Published: January 2022

With the continuous enrichment of social network applications, such as TikTok, Weibo, Twitter, and others, social media have become an indispensable part of our lives. Web users can participate in their favorite events or pay attention to people they like. The “heterogeneous” influence between events and users can be effectively modeled, and users’ potential future behaviors can be predicted, so as to facilitate applications such as recommendations and online advertising. For example, a user’s favorite live streaming host (user) recommends certain products (event), can we predict whether the user will buy these products in the future? The majority of studies are based on a homogeneous graph neural network to model the influence between users. However, these studies ignore the impact of events on users in reality. For instance, when users purchase commodities through live streaming channels, in addition to the factors of the host, the commodity is also a key factor that influences the behavior of users. This study designs an influence prediction model based on a heterogeneous neural network HetInf. Specifically, we first constructed the heterogeneous social influence network according to the relationship between event nodes and user nodes, then sampled the user heterogeneous subgraph for each user, extracted the relevant node features, and finally predicted the probability of user behavior through the heterogeneous neural network model. We conducted comprehensive experiments on two large social network datasets. Furthermore, the experimental results show that HetInf is significantly superior to the previous homogeneous neural network methods.
The Impact of Cardiac Rehabilitation on Activities of Daily Life in Elderly Patients With Heart Failure
Authors: Paneroni Mara , Scalvini Simonetta , Corrà Ugo , Lovagnini Marta , Maestri Roberto , Mazza Antonio , Raimondo Rosa , Agostoni Piergiuseppe , La Rovere Maria Teresa
Published: January 2022

Background: In elderly chronic heart failure (HF) patients, activities of daily living (ADLs) require the use of a high proportion of patients’ peak aerobic capacity, heart rate, and ventilation.

Objectives: To assess the effects of short-term comprehensive cardiac rehabilitation (CR) on the metabolic requirement of ADLs in elderly patients with chronic HF.

Methods: The study population comprised 99 elderly chronic HF patients (mean age 72 ± 5 years, 80% male, 61% ejection fraction <40%, mean NT-proBNP 2,559 ± 4,511 pg/ml) participating in a short-term (mean days 19 ± 7) residential CR program. Before and after CR, participants, while wearing a portable ergospirometer, performed a standardized ADL battery: ADL1 (getting dressed), ADL2 (folding 8 towels), ADL3 (putting away 6 bottles), ADL4 (making a bed), ADL5 (sweeping the floor for 4 min), ADL6 (climbing 1 flight of stairs carrying a 1.5 Kg load), and ADL7 (a standard 6-min walking test).

Results: After CR, task-related oxygen uptake did not change in any of the domestic ADLs. Notably, there was a significant decrease in the cumulative time required to perform ADLs (ADL 1–4 and ADL6; from 412 ± 147 to 388 ± 141 s, p = 0.001) and a reduction in maximal heart rate in ADL1 and 3 (p = 0.005 and p = 0.027, respectively). Changes occurred in the 6MWT with an increase in oxygen uptake (p = 0.005) and in the distance covered (p < 0.001) and a significant decrease in the Borg scale of dyspnea (p = 0.004).

Conclusion: Elderly patients with chronic heart failure who are engaged in a short-term residential CR program improve the performance of routine ADLs.
Supervised Cycling Training Improves Erythrocyte Rheology in Individuals With Peripheral Arterial Disease
Authors: Hsu Chih-Chin , Lin Yu-Ting , Fu Tieh-Cheng , Huang Shu-Chun , Lin Cheng-Hsien , Wang Jong-Shyan
Published: January 2022

Peripheral arterial disease (PAD) results in insufficient flow to lower extremities. Aerobic exercise provides health benefits for individuals with PAD, but basic science behind it is still debated. Twenty-one PAD patients aged about 70 years with female/male as 7/14 were recruited. Among them, 11 were randomized to have supervised cycling training (SCT) and 10 to receive general healthcare (GHC) as controls. SCT participants completed 36 sessions of SCT at the first ventilation threshold within 12 weeks and the controls received GHC for 12 weeks. Ankle-brachial index (ABI), 6-min walk test (6MWT), peak oxygen consumption (V˙O2peak), minute ventilation (V˙E), minute carbon dioxide production (V˙CO2), erythrocyte rheology, including the maximal elongation index (EImax) and shear stress at 50% of maximal elongation (SS1/2), and the Short Form-36 (SF-36) questionnaire for quality of life (QoL) were assessed before and 12 weeks after initial visit. SCT significantly decreased the SS1/2 as well as SS1/2 to EImax ratio (SS1/2/EImax) and increased the erythrocyte osmolality in the hypertonic region as well as the area under EI-osmolality curve. The supervised exercise-induced improvement of erythrocyte deformability could contribute to the increased peripheral tissue O2 delivery and was possibly related with increased V˙O2peak. The physiological benefit was associated with significantly increased ABI, 6-min walking distance, cardiorespiratory fitness, and SF-36 score. However, no significant changes in aerobic capacity and erythrocyte rheological properties were observed after 12-week of GHC. In conclusion, SCT improves aerobic capacity by enhancing erythrocyte membrane deformability and consequently promotes QoL in PAD patients.
Relationship Between Circulating Metabolic Hormones and Their Central Receptors During Ovariectomy-Induced Weight Gain in Rats
Authors: Burch Kaitlin E. , McCracken Kelly , Buck Daniel J. , Davis Randall L. , Sloan Dusti K. , Curtis Kathleen S.
Published: January 2022

Although increasing research focuses on the phenomenon of body weight gain in women after menopause, the complexity of body weight regulation and the array of models used to investigate it has proven to be challenging. Here, we used ovariectomized (OVX) rats, which rapidly gain weight, to determine if receptors for ghrelin, insulin, or leptin in the dorsal vagal complex (DVC), arcuate nucleus (ARC), or paraventricular nucleus (PVN) change during post-ovariectomy weight gain. Female Sprague-Dawley rats with ad libitum access to standard laboratory chow were bilaterally OVX or sham OVX. Subgroups were weighed and then terminated on day 5, 33, or 54 post-operatively; blood and brains were collected. ELISA kits were used to measure receptors for ghrelin, insulin, and leptin in the DVC, ARC, and PVN, as well as plasma ghrelin, insulin, and leptin. As expected, body weight increased rapidly after ovariectomy. However, ghrelin receptors did not change in any of the areas for either group, nor did circulating ghrelin. Thus, the receptor:hormone ratio indicated comparable ghrelin signaling in these CNS areas for both groups. Insulin receptors in the DVC and PVN decreased in the OVX group over time, increased in the PVN of the Sham group, and were unchanged in the ARC. These changes were accompanied by elevated circulating insulin in the OVX group. Thus, the receptor:hormone ratio indicated reduced insulin signaling in the DVC and PVN of OVX rats. Leptin receptors were unchanged in the DVC and ARC, but increased over time in the PVN of the Sham group. These changes were accompanied by elevated circulating leptin in both groups that was more pronounced in the OVX group. Thus, the receptor:hormone ratio indicated reduced leptin signaling in the DVC and PVN of both groups, but only in the OVX group for the ARC. Together, these data suggest that weight gain that occurs after removal of ovarian hormones by ovariectomy is associated with selective changes in metabolic hormone signaling in the CNS. While these changes may reflect behavioral or physiological alterations, it remains to be determined whether they cause post-ovariectomy weight gain or result from it.
Association of ZFHX3 Genetic Polymorphisms and Extra-Pulmonary Vein Triggers in Patients With Atrial Fibrillation Who Underwent Catheter Ablation
Authors: Hwang Inseok , Kwon Oh-Seok , Hong Myunghee , Yang Song-Yi , Park Je-Wook , Yu Hee Tae , Kim Tae-Hoon , Uhm Jae-Sun , Joung Boyoung , Lee Moon-Hyoung , Pak Hui-Nam
Published: January 2022

Background: The ZFHX3 gene (16q22) is the second most highly associated gene with atrial fibrillation (AF) and is related to inflammation and fibrosis. We hypothesized that ZFHX3 is associated with extra-pulmonary vein (PV) triggers, left atrial (LA) structural remodeling, and poor rhythm outcomes of AF catheter ablation (AFCA).

Methods: We included 1,782 patients who underwent a de novo AFCA (73.5% male, 59.4 ± 10.8 years old, 65.9% paroxysmal AF) and genome-wide association study and divided them into discovery (n = 891) and replication cohorts (n = 891). All included patients underwent isoproterenol provocation tests and LA voltage mapping. We analyzed the ZFHX3, extra-PV trigger-related factors, and rhythm outcomes.

Result: Among 14 single-nucleotide polymorphisms (SNPs) of ZFHX3, rs13336412, rs61208973, rs2106259, rs12927436, and rs1858801 were associated with extra-PV triggers. In the overall patient group, extra-PV triggers were independently associated with the ZFHX3 polygenic risk score (PRS) (OR 1.65 [1.22–2.22], p = 0.001, model 1) and a low LA voltage (OR 0.74 [0.56–0.97], p = 0.029, model 2). During 49.9 ± 40.3 months of follow-up, clinical recurrence of AF was significantly higher in patients with extra-PV triggers (Log-rank p < 0.001, HR 1.89 [1.49–2.39], p < 0.001, model 1), large LA dimensions (Log-rank p < 0.001, HR 1.03 [1.01–1.05], p = 0.002, model 2), and low LA voltages (Log-rank p < 0.001, HR 0.73 [0.61–0.86], p < 0.001, model 2) but not the ZFHX3 PRS (Log-rank p = 0.819).

Conclusion: The extra-PV triggers had significant associations with both ZFHX3 genetic polymorphisms and acquired LA remodeling. Although extra-PV triggers were an independent predictor of AF recurrence after AFCA, the studied AF risk SNPs intronic in ZFHX3 were not associated with AF recurrence.
Drought Tolerant Near Isogenic Lines of Pusa 44 Pyramided With qDTY2.1 and qDTY3.1, Show Accelerated Recovery Response in a High Throughput Phenomics Based Phenotyping
Authors: Dwivedi Priyanka , Ramawat Naleeni , Raju Dhandapani , Dhawan Gaurav , Gopala Krishnan S. , Chinnusamy Viswanathan , Bhowmick Prolay Kumar , Vinod K. K. , Pal Madan , Nagarajan Mariappan , Ellur Ranjith Kumar , Bollinedi Haritha , Singh Ashok K.
Published: January 2022

Reproductive stage drought stress (RSDS) is a major challenge in rice production worldwide. Cultivar development with drought tolerance has been slow due to the lack of precise high throughput phenotyping tools to quantify drought stress-induced effects. Most of the available techniques are based on destructive sampling and do not assess the progress of the plant’s response to drought. In this study, we have used state-of-the-art image-based phenotyping in a phenomics platform that offers a controlled environment, non-invasive phenotyping, high accuracy, speed, and continuity. In rice, several quantitative trait loci (QTLs) which govern grain yield under drought determine RSDS tolerance. Among these, qDTY2.1 and qDTY3.1 were used for marker-assisted breeding. A set of 35 near-isogenic lines (NILs), introgressed with these QTLs in the popular variety, Pusa 44 were used to assess the efficiency of image-based phenotyping for RSDS tolerance. NILs offered the most reliable contrast since they differed from Pusa 44 only for the QTLs. Four traits, namely, the projected shoot area (PSA), water use (WU), transpiration rate (TR), and red-green-blue (RGB) and near-infrared (NIR) values were used. Differential temporal responses could be seen under drought, but not under unstressed conditions. NILs showed significant level of RSDS tolerance as compared to Pusa 44. Among the traits, PSA showed strong association with yield (80%) as well as with two drought tolerances indices, stress susceptibility index (SSI) and tolerance index (TOL), establishing its ability in identifying the best drought tolerant NILs. The results revealed that the introgression of QTLs helped minimize the mean WU per unit of biomass per day, suggesting the potential role of these QTLs in improving WU-efficiency (WUE). We identified 11 NILs based on phenomics traits as well as performance under imposed drought in the field. The study emphasizes the use of phenomics traits as selection criteria for RSDS tolerance at an early stage, and is the first report of using phenomics parameters in RSDS selection in rice.