bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic Implications of Ferroptosis in Renal Fibrosis
Authors: Zhang Yao , Mou Yanhua , Zhang Jianjian , Suo Chuanjian , Zhou Hai , Gu Min , Wang Zengjun , Tan Ruoyun
Published: May 2022

Renal fibrosis is a common feature of chronic kidney disease (CKD), and can lead to the destruction of normal renal structure and loss of kidney function. Little progress has been made in reversing fibrosis in recent years. Ferroptosis is more immunogenic than apoptosis due to the release and activation of damage-related molecular patterns (DAMPs) signals. In this paper, the relationship between renal fibrosis and ferroptosis was reviewed from the perspective of iron metabolism and lipid peroxidation, and some pharmaceuticals or chemicals associated with both ferroptosis and renal fibrosis were summarized. Other programmed cell death and ferroptosis in renal fibrosis were also firstly reviewed for comparison and further investigation.
Intermittent Theta Burst Stimulation Ameliorates Cognitive Deficit and Attenuates Neuroinflammation via PI3K/Akt/mTOR Signaling Pathway in Alzheimer’s-Like Disease Model
Authors: Stekic Andjela , Zeljkovic Milica , Zaric Kontic Marina , Mihajlovic Katarina , Adzic Marija , Stevanovic Ivana , Ninkovic Milica , Grkovic Ivana , Ilic Tihomir V. , Nedeljkovic Nadezda , Dragic Milorad
Published: May 2022

Neurodegeneration implies progressive neuronal loss and neuroinflammation further contributing to pathology progression. It is a feature of many neurological disorders, most common being Alzheimer’s disease (AD). Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive stimulation which modulates excitability of stimulated brain areas through magnetic pulses. Numerous studies indicated beneficial effect of rTMS in several neurological diseases, including AD, however, exact mechanism are yet to be elucidated. We aimed to evaluate the effect of intermittent theta burst stimulation (iTBS), an rTMS paradigm, on behavioral, neurochemical and molecular level in trimethyltin (TMT)-induced Alzheimer’s-like disease model. TMT acts as a neurotoxic agent targeting hippocampus causing cognitive impairment and neuroinflammation, replicating behavioral and molecular aspects of AD. Male Wistar rats were divided into four experimental groups–controls, rats subjected to a single dose of TMT (8 mg/kg), TMT rats subjected to iTBS two times per day for 15 days and TMT sham group. After 3 weeks, we examined exploratory behavior and memory, histopathological and changes on molecular level. TMT-treated rats exhibited severe and cognitive deficit. iTBS-treated animals showed improved cognition. iTBS reduced TMT-induced inflammation and increased anti-inflammatory molecules. We examined PI3K/Akt/mTOR signaling pathway which is involved in regulation of apoptosis, cell growth and learning and memory. We found significant downregulation of phosphorylated forms of Akt and mTOR in TMT-intoxicated animals, which were reverted following iTBS stimulation. Application of iTBS produces beneficial effects on cognition in of rats with TMT-induced hippocampal neurodegeneration and that effect could be mediated via PI3K/Akt/mTOR signaling pathway, which could candidate this protocol as a potential therapeutic approach in neurodegenerative diseases such as AD.
The Legacy of the TTASAAN Report – Premature Conclusions and Forgotten Promises About SPECT Neuroimaging: A Review of Policy and Practice Part II
Authors: Pavel Dan G. , Henderson Theodore A. , DeBruin Simon , Cohen Philip F.
Published: May 2022

Brain perfusion single photon emission computed tomography (SPECT) scans were initially developed in 1970s. A key radiopharmaceutical, hexamethylpropyleneamine oxime (HMPAO), was not stabilized until 1993 and most early SPECT scans were performed on single-head gamma cameras. These early scans were of inferior quality. In 1996, the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (TTASAAN) issued a report regarding the use of SPECT in the evaluation of neurological disorders. This two-part series explores the policies and procedures related to perfusion SPECT functional neuroimaging. In Part I, the comparison between the quality of the SPECT scans and the depth of the data for key neurological and psychiatric indications at the time of the TTASAAN report vs. the intervening 25 years were presented. In Part II, the technical aspects of perfusion SPECT neuroimaging and image processing will be explored. The role of color scales will be reviewed and the process of interpreting a SPECT scan will be presented. Interpretation of a functional brain scans requires not only anatomical knowledge, but also technical understanding on correctly performing a scan, regardless of the scanning modality. Awareness of technical limitations allows the clinician to properly interpret a functional brain scan. With this foundation, four scenarios in which perfusion SPECT neuroimaging, together with other imaging modalities and testing, lead to a narrowing of the differential diagnoses and better treatment. Lastly, recommendations for the revision of current policies and practices are made.
Intracranial Aneurysms Induced by RUNX1 Through Regulation of NFKB1 in Patients With Hypertension-An Integrated Analysis Based on Multiple Datasets and Algorithms
Authors: Li Yang , Zhang Zhen , Liu Donghua
Published: May 2022

Objective

The purpose of this study was to identify potential therapeutic targets by examining the hub genes contributing to progression of intracranial aneurysm (IA) in patients with hypertension.

Methods

The bulk RNA sequencing (RNA-seq) datasets of hypertension and IA were obtained from the Gene Expression Omnibus (www.ncbi.nlm.nih.gov/geo) database. These data were then used to calculate disease-related differentially expressed genes (DEGs) at the individual level. An scRNA-seq dataset of patients with abdominal aortic aneurysms (AAA) was used to analyze monocyte/macrophage-related DEGs. On the basis of the DEG data related to monocytes and macrophages, a TF-genes network has been developed. Hub genes and core sub-networks have also been identified. Furthermore, the key genes have been validated in an external cohort.

Results

From combined monocyte and macrophage-derived DEGs from abdominal aortic aneurysms, five hub DEGs were detected, including IFI30, SERPINE1, HMOX1, IL24, and RUNX1. A total of 57 genes were found in the IA bulk RNA-seq dataset. A support vector machine-recursive feature elimination algorithm (SVM-RFE) was applied to further screen the seven genes (RPS4Y1, DDX3Y, RUNX1, CLEC10A, PLAC8, SLA, and LILRB3). RUNX1 was the hub gene that regulated NFKB1 in the monocyte/macrophage-related network. And RUNX1 is implicated in IA progression by regulating hematopoietic stem cell differentiation and abnormal platelet production, according to gene set enrichment analysis.

Conclusion

Among patients with hypertension, RUNX1 in monocytes and macrophages was associated with a higher risk of IA through its regulation of NFKB1.
The Role of Neck Input in Producing Corrective Saccades in the Head Impulse Test
Authors: Iwasaki Shinichi , Kamogashira Teru , Fujimoto Chisato , Kabaya Kayoko , Kinoshita Makoto , Yamasoba Tatsuya
Published: May 2022

Background

The head impulse test is a valuable clinical test that can help identify peripheral vestibular dysfunction by observing corrective saccades that return the eyes to the target of interest. Corrective saccades have been classified as covert if the onset occurs before the end of the head impulse and as overt if they occur afterwards. However, the mechanism that trigger these saccades remain unclear.

Objective

The objective of this study was to examine the role of neck input in generating overt as well as covert saccades.

Methods

Sixteen patients (9 males and 7 females: age 35-80 years, average 62.7 years old) who showed corrective saccades during the head impulse test were included. Twelve patients had unilateral vestibular dysfunction, and 4 patients had bilateral vestibular dysfunction. Patients underwent both the head impulse test (HIT) and the body impulse test (BIT) in a randomized order. While the head is rotated horizontally in HIT, the body is rotated horizontally in BIT. During BIT, the neck is fixed by a cervical collar (neck lock extrication collar) to reduce somatosensory input from the neck. The head movements and eye movements were recorded and analyzed by the video HIT recording system.

Results

In all 16 patients, corrective saccades were observed in HIT as well as in BIT. While there were no significant differences in peak head velocities between HIT and BIT (p = 0.33, paired t-test), the VOR gain in BIT was significantly smaller than that in HIT (p = 0.011, paired t-test). The number of overt saccades per trial in BIT was significantly decreased compared to that in HIT (p < 0.001, paired t-test) whereas there were no significant differences in the number of covert saccades between the two tests. The proportion of overt saccades among all corrective saccades in BIT was significantly lower than the proportion in HIT (p < 0.001, paired t-test).

Conclusions

Somatosensory input from the neck contributes to the generation of overt saccades and reinforces the vestibulo-ocular reflex complementing the retinal slip during high frequency head movements.
Cerebellar Abnormalities on Proton MR Spectroscopy and Imaging in Patients With Gluten Ataxia: A Pilot Study
Authors: Rawat Vishwa , Tyagi Ritu , Singh Inder , Das Prasenjit , Srivastava Achal Kumar , Makharia Govind K. , Sharma Uma
Published: May 2022

Gluten ataxia is a rare immune-mediated neurological disorder caused by the ingestion of gluten. The diagnosis is not straightforward as antibodies are present in only up to 38% of patients, but often at lower titers. The symptoms of ataxia may be mild at the onset but lead to permanent damage if remain untreated. It is characterized by damage to the cerebellum however, the pathophysiology of the disease is not clearly understood. The present study investigated the neurochemical profile of vermis and right cerebellum and structural changes in various brain regions of patients with gluten ataxia (n = 6, age range 40–65 years) and compared it with healthy controls (n = 10, 40–55 years). Volumetric 3-D T1 and T1-weighted magnetic resonance imaging (MRI) in the three planes (axial, coronal, and sagittal) of the whole brain and single-voxel 1H- magnetic resonance spectroscopy (MRS) of the vermis and right cerebellum were acquired on 3 T human MR scanner. The metabolite concentrations were estimated using LC Model (6.1–4A) while brain volumes were estimated using the online tool volBrain pipeline and CERES and corrected for partial volumes. The levels of neuro-metabolites (N-acetyl aspartate + N-acetyl aspartate glutamate, glycerophosphocholine + phosphocholine, and total creatine) were found to be significantly lower in vermis, while N-acetyl aspartate + N-acetyl aspartate glutamate and glycerophosphocholine + phosphocholine was lower in cerebellum regions in the patients with gluten ataxia compared to healthy controls. A significant reduction in the white matter of (total brain, cerebellum, and cerebrum); reduction in the volumes of cerebellum lobe (X) and thalamus while lateral ventricles were increased in the patients with gluten ataxia compared to healthy controls. The reduced neuronal metabolites along with structural changes in the brain suggested neuronal degeneration in the patients with gluten ataxia. Our preliminary findings may be useful in understanding the gluten-induced cerebral damage and indicated that MRI and MRS may serve as a non-invasive useful tool in the early diagnosis, thereby enabling better management of these patients.
Bidirectional Optogenetic Modulation of the Subthalamic Nucleus in a Rodent Model of Parkinson’s Disease
Authors: Xie Caroline , Power John , Prasad Asheeta A.
Published: May 2022

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a range of motor symptoms. Treatments are focused on dopamine replacement therapy or deep brain stimulation (DBS). The subthalamic nucleus (STN) is a common target for DBS treatment of PD. However, the function of the STN in normal conditions and pathology is poorly understood. Here, we show in rats that optogenetic modulation of STN neuronal activity exerts bidirectional control of motor function, where inhibition of the STN increases movement and STN activation decreases movement. We also examined the effect of bidirectional optogenetic manipulation STN neuronal activity under dopamine depleted condition using the bilateral rodent 6-hydroxydopamine (6-OHDA) model of Parkinson’s disease. Optogenetic inhibition of the STN in the absence of dopamine had no impact on motor control yet STN excitation led to pronounced abnormal involuntary movement. Administration of levodopa rescued the abnormal involuntary movements induced by STN excitation. Although dopamine and STN dysfunction are well established in PD pathology, here we demonstrate simultaneous STN over activity and loss of dopamine lead to motor deficits. Moreover, we show the dysfunction of the STN is dependent on dopamine. This study provides evidence that the loss of dopamine and the over activity of the STN are key features of PD motor deficits. These results provide insight into the STN pathology in PD and therapeutic mechanism of targeting the STN for the treatment for PD.
Auditory Mismatch Responses to Emotional Stimuli in 3-Year-Olds in Relation to Prenatal Maternal Depression Symptoms
Authors: Luotonen Silja , Railo Henry , Acosta Henriette , Huotilainen Minna , Lavonius Maria , Karlsson Linnea , Karlsson Hasse , Tuulari Jetro J.
Published: May 2022

Maternal depression symptoms are common in pregnant women and can have negative effects on offspring’s emotional development. This study investigated the association between prenatal maternal depression symptoms (assessed with the Edinburgh Postnatal Depression Scale at 24 weeks of gestation) and auditory perception of emotional stimuli in 3-year-olds (n = 58) from the FinnBrain Birth Cohort Study. Using electroencephalography (EEG), we examined mismatch responses for happy, sad, and angry sounds presented among neutral stimuli. A positive association between maternal depression symptoms and the emotional mismatch responses in an early time window (80–120 ms) was found, indicating that brain responses of children of mothers with depressive symptoms were weaker to happy sounds, though the results did not survive Bonferroni correction. There were no clear associations in the sad and angry emotional categories. Our results tentatively support that the 3-year-old children of mothers with depression symptoms may be less sensitive to automatically detect happy sounds compared to children whose mothers do not display symptoms of depression.
SHROOM4 Variants Are Associated With X-Linked Epilepsy With Features of Generalized Seizures or Generalized Discharges
Authors: Bian Wen-Jun , Li Zong-Jun , Wang Jie , Luo Sheng , Li Bing-Mei , Gao Liang-Di , He Na , Yi Yong-Hong
Published: May 2022

Objective

SHROOM4 gene encodes an actin-binding proteins, which plays an important role in cytoskeletal architecture, synaptogenesis, and maintaining gamma-aminobutyric acid receptors-mediated inhibition. SHROOM4 mutations were reported in patients with the Stocco dos Santos type of X-linked syndromic intellectual developmental disorder (SDSX; OMIM# 300434). In this study, we investigated the association between SHROOM4 and epilepsy.

Methods

Trios-based whole-exome sequencing was performed in a cohort of 320 cases with idiopathic generalized epilepsy or idiopathic partial epilepsy. Protein modeling was used to assess the damaging effects of variations.

Results

Six hemizygous missense SHROOM4 variants, including c.13C > A/p. Pro5Thr, c.3236C > T/p.Glu1079Ala, c.3581C > T/p.Ser1194Leu, c.4288C > T/p.Arg1430Cys, c.4303G > A/p.Val1435Met, c.4331C > T/p.Pro1444Leu, were identified in six cases with idiopathic epilepsy without intellectual disability. All patients presented with features of generalized seizures or generalized discharges. These hemizygous variants had no or extremely low allele frequencies in controls and showed statistically higher frequency in the case cohort than controls. All variants were predicted to alter hydrogen bond with surrounding amino acids or decreased protein stability. The SHROOM4 variants reported in patients with SDSX were mostly destructive or duplicative variants; in contrast, the SHROOM4 variants were all missense variants, suggesting a potential genotype-phenotype correlation. The two missense variants associated with SDSX were located in the middle of SHROOM4 protein, whereas variants associated with idiopathic epilepsy were located around the N-terminal PDZ domain and the C-terminal ASD2 domain.

Significance

SHROOM4 was potentially a candidate pathogenic gene of idiopathic epilepsy without intellectual disability. The genotype-phenotype correlation and sub-regional effect helps understanding the mechanism underlying phenotypic variation.
Cigarette Smoke Exposure Induces Neurocognitive Impairments and Neuropathological Changes in the Hippocampus
Authors: Dobric Aleksandar , De Luca Simone N. , Seow Huei Jiunn , Wang Hao , Brassington Kurt , Chan Stanley M. H. , Mou Kevin , Erlich Jonathan , Liong Stella , Selemidis Stavros , Spencer Sarah J. , Bozinovski Steven , Vlahos Ross
Published: May 2022

Background and Objective

Neurocognitive dysfunction is present in up to ∼61% of people with chronic obstructive pulmonary disease (COPD), with symptoms including learning and memory deficiencies, negatively impacting the quality of life of these individuals. As the mechanisms responsible for neurocognitive deficits in COPD remain unknown, we explored whether chronic cigarette smoke (CS) exposure causes neurocognitive dysfunction in mice and whether this is associated with neuroinflammation and an altered neuropathology.

Methods

Male BALB/c mice were exposed to room air (sham) or CS (9 cigarettes/day, 5 days/week) for 24 weeks. After 23 weeks, mice underwent neurocognitive tests to assess working and spatial memory retention. At 24 weeks, mice were culled and lungs were collected and assessed for hallmark features of COPD. Serum was assessed for systemic inflammation and the hippocampus was collected for neuroinflammatory and structural analysis.

Results

Chronic CS exposure impaired lung function as well as driving pulmonary inflammation, emphysema, and systemic inflammation. CS exposure impaired working memory retention, which was associated with a suppression in hippocampal microglial number, however, these microglia displayed a more activated morphology. CS-exposed mice showed changes in astrocyte density as well as a reduction in synaptophysin and dendritic spines in the hippocampus.

Conclusion

We have developed an experimental model of COPD in mice that recapitulates the hallmark features of the human disease. The altered microglial/astrocytic profiles and alterations in the neuropathology within the hippocampus may explain the neurocognitive dysfunction observed during COPD.
A Cross-Sectional Study of the Distribution Patterns and Potential Determinants in Plasma Selenium Status Among Chinese Adults With Hypertension
Authors: Wang Zhuo , Lin Tengfei , Wei Yaping , Song Yun , Liu Lishun , Zhou Ziyi , Huang Xiao , Chen Ping , Liu Chengzhang , Li Youbao , Wang Binyan , Li Jianping , Zhang Yan , Huo Yong , Zhang Hao , Xu Xiping , Qin Xianhui , Guo Huiyuan
Published: May 2022

Selenium (Se) is an essential trace element in selenoproteins biosynthesis for the human body and plays an important role in the prevention and control of subsequent cardiovascular disease in adults with hypertension. However, reports on Se status and its potential determinants in populations from different regions of China are limited, especially data on adults with hypertension, a high-risk group more vulnerable to oxidative stress. Thus, we conducted a cross-sectional study from February 2017 to May 2018 of 2,599 participants (1,389 men and 1,210 women) on middle-aged to elderly adults with hypertension with a mean age of 63.1 years (SD 13.3) from 14 provinces of China and aimed to examine the relationship of plasma Se status with demographic characteristics and lifestyles. Overall, the male participants (mean value 75.0 μg/L) tended to have higher plasma Se concentrations than the female participants (73.7 μg/L) when controlling for relevant factors. There were significant differences among regions, and in age and body mass index (BMI) in plasma Se distribution, and plasma Se concentrations were significantly lower among those in the regions with relatively lower Se, aged 60 years or older, and with BMI lower than 28 kg/m2. Moreover, a higher frequency of meat consumption (1–2 or ≥3 times/week vs. <1 time/week) was significantly associated with higher plasma Se concentrations in men and women, and male alcohol drinkers had significantly higher plasma Se concentrations than non-alcohol drinkers. Adequate consumption of fruits and vegetables (0.5–1.5 kg/week) was associated with higher plasma Se concentrations among women, but was associated with relatively lower plasma Se concentrations in men. Our results indicated relatively low plasma Se status in Chinese adults with hypertension from 14 provinces, while specific factors including geographic, demographic, and lifestyle characteristics and blood pressure were significantly associated with plasma Se status in this hypertensive population. In addition, more studies are required to further evaluate dietary structure and other lifestyle factors that influence circulating Se status.
NSAID Treatment Before and on the Early Onset of Acute Kidney Injury Had an Opposite Effect on the Outcome of Patients With AKI
Authors: Wang Hai , Liu Tong , Li Qinglin , Cui Ruixia , Fan Xueying , Tong Yingmu , Ma Shuzhen , Liu Chang , Zhang Jingyao
Published: May 2022

Background: NSAIDs are one of the most frequently used medications and a risk factor for AKI. However, the optimal time of NSAIDs in patients with AKI is unknown.

Methods: A secondary analysis of a multicenter, randomized clinical trial including adult inpatients with acute kidney injury was performed. Univariate, multivariate, and subgroup analyses were used to explore the impact of NSAIDs during the early onset of AKI on the outcome of patients with AKI.

Results: A total of 6,030 patients with AKI were enrolled in the study. Following are the findings of the multi-factor analysis: NSAID treatments within 72 and 24 h before the onset of AKI were not associated with AKI progression, dialysis, or discharge from dialysis; only NSAID treatment within the 24-h onset of AKI was associated with these outcomes, and their OR values were independently 1.50 (95% CI: 1.02–2.19, p = 0.037), 4.20 (95% CI: 1.47–11.97, p = 0.007), and 0.71 (95% CI: 0.54–0.92, p = 0.011); only NSAID treatment within the 24-h onset of AKI would decrease the 14-day mortality, and the OR value was 0.52 (95% CI: 0.33–0.82, p = 0.005). The subgroup analysis revealed that in patients with age ≥65 years, CKD (chronic kidney disease), congestive heart failure, hypertension, and liver disease, NSAID treatments within the 24-h onset of AKI would deteriorate the outcome of patients with AKI.

Conclusion: Before an early onset of AKI, NSAID treatment might be safe, but during the onset of AKI, even early NSAID treatment would deteriorate the outcome of patients with AKI.
Resibufogenin Targets the ATP1A1 Signaling Cascade to Induce G2/M Phase Arrest and Inhibit Invasion in Glioma
Authors: Zhang Xun , Yao Zhong , Xue Zhiyi , Wang Shuai , Liu Xuemeng , Hu Yaotian , Zhang Yan , Wang Jian , Li Xingang , Chen Anjing
Published: May 2022

Resibufogenin (RB) is a major active ingredient in the traditional Chinese medicine Chansu and has garnered considerable attention for its efficacy in the treatment of cancer. However, the anticancer effects and underlying mechanisms of RB on glioblastoma (GBM) remain unknown. Here, we found that RB induced G2/M phase arrest and inhibited invasion in a primary GBM cell line, P3#GBM, and two GBM cell lines, U251 and A172. Subsequently, we demonstrated that RB-induced G2/M phase arrest occurred through downregulation of CDC25C and upregulation of p21, which was caused by activation of the MAPK/ERK pathway, and that RB inhibited GBM invasion by elevating intercellular Ca2+ to suppress the Src/FAK/Paxillin focal adhesion pathway. Intriguingly, we confirmed that upon RB binding to ATP1A1, Na+-K+-ATPase was activated as a receptor and then triggered the intracellular MAPK/ERK pathway and Ca2+-mediated Src/FAK/Paxillin focal adhesion pathway, which led to G2/M phase arrest and inhibited the invasion of GBM cells. Taken together, our findings reveal the antitumor mechanism of RB by targeting the ATP1A1 signaling cascade and two key signaling pathways and highlight the potential of RB as a new class of promising anticancer agents.
Comprehensive Analysis of a Ferroptosis Pattern and Associated Prognostic Signature in Acute Myeloid Leukemia
Authors: Cui Zelong , Fu Yue , Yang Zongcheng , Gao Zhenxing , Feng Huimin , Zhou Minran , Zhang Lu , Chen Chunyan
Published: May 2022

Ferroptosis is a widespread form of programmed cell death. The environment of cancer cells makes them vulnerable to ferroptosis, including AML cells, yet the specific association between ferroptosis and AML outcome is little known. In this study, we utilized ferroptosis-related genes to distinguish two subtypes in TCGA cohort, which were subsequently validated in independent AML cohorts. The subtypes were linked with tumor-related immunological abnormalities, mutation landscape and pathway dysregulation, and clinical outcome. Further, we developed a 13-gene prognostic model for AML from DEG analysis in the two subtypes. A risk score was calculated for each patient, and then the overall group was stratified into high- and low-risk groups; the higher risk score correlated with short survival. The model was validated in both independent AML cohorts and pan-cancer cohorts, which demonstrated robustness and extended the usage of the model. A nomogram was constructed that integrated risk score, FLT3-ITD, TP53, and RUNX1 mutations, and age. This model had the additional value of discriminating the sensitivity of several chemotherapeutic drugs and ferroptosis inducers in the two risk groups, which increased the translational value of this model as a potential tool in clinical management. Through integrated analysis of ferroptosis pattern and its related model, our work shed new light on the relationship between ferroptosis and AML, which may facilitate clinical application and therapeutics.
Network Pharmacology and Experimental Verification Strategies to Illustrate the Mechanism of Jian-Pi-Yi-Shen Formula in Suppressing Epithelial–Mesenchymal Transition
Authors: Zhao Yuan , Li Xiangbin , Wang Fochang , Huang Shiying , Du Hanqian , Li Shunmin , Chen Jianping
Published: May 2022

Jian-Pi-Yi-Shen formula (JPYSF), a traditional Chinese medicine, has been recommended to treat renal fibrosis for decades. Previous studies had shown that JPYSF could inhibit epithelial–mesenchymal transition (EMT), an important regulatory role in renal fibrosis. However, the mechanism of JPYSF action is largely unknown. In this study, network pharmacology and experimental verification were combined to elucidate and identify the potential mechanism of JPYSF against renal fibrosis by suppressing EMT at molecular and pathway levels. Network pharmacology was first performed to explore the mechanism of JPYSF against renal fibrosis targeting EMT, and then a 5/6 nephrectomy (5/6 Nx)-induced rat model of renal fibrosis was selected to verify the predictive results by Masson’s trichrome stains and western blot analysis. Two hundred and thirty-two compounds in JPYSF were selected for the network approach analysis, which identified 137 candidate targets of JPYSF and 4,796 known therapeutic targets of EMT. The results of the Gene Ontology (GO) function enrichment analysis included 2098, 88, and 133 GO terms for biological processes (BPs), molecular functions (MFs), and cell component entries, respectively. The top 10 enrichment items of BP annotations included a response to a steroid hormone, a metal ion, oxygen levels, and so on. Cellular composition (CC) is mainly enriched in membrane raft, membrane microdomain, membrane region, etc. The MF of JPYSF analysis on EMT was predominately involved in proximal promoter sequence-specific DNA binding, protein heterodimerization activity, RNA polymerase II proximal promoter sequence-specific DNA binding, and so on. The involvement signaling pathway of JPYSF in the treatment of renal fibrosis targeting EMT was associated with anti-fibrosis, anti-inflammation, podocyte protection, and metabolism regulation. Furthermore, the in vivo experiments confirmed that JPYSF effectively ameliorated interstitial fibrosis and inhibited the overexpression of α-SMA, Wnt3a, and β-catenin, and increased the expression of E-cadherin by wnt3a/β-catenin signaling pathway in 5/6 Nx-induced renal fibrosis rats. Using an integrative network pharmacology-based approach and experimental verification, the study showed that JPYSF had therapeutic effects on EMT by regulating multi-pathway, among which one proven pathway was the Wnt3a/β-catenin signaling pathway. These findings provide insights into the renoprotective effects of JPYSF against EMT, which could suggest directions for further research of JPYSF in attenuating renal fibrosis by suppressing EMT.
Membrane Attack Complex C5b-9 Promotes Renal Tubular Epithelial Cell Pyroptosis in Trichloroethylene-Sensitized Mice
Authors: Wang Feng , Huang Meng , Wang Yican , Hong Yiting , Zang Dandan , Yang Chunjun , Wu Changhao , Zhu Qixing
Published: May 2022

Trichloroethylene (TCE), a commonly used organic solvent, is known to cause trichloroethylene hypersensitivity syndrome (THS), also called occupational medicamentosa–like dermatitis due to TCE (OMDT) in China. OMDT patients presented with severe inflammatory kidney damage, and we have previously shown that the renal damage is related to the terminal complement complex C5b-9. Here, we sought to determine whether C5b-9 participated in TCE-induced immune kidney injury by promoting pyroptosis, a new form of programed cell death linked to inflammatory response, with underlying molecular mechanisms involving the NLRP3 inflammasome. A BALB/c mouse-based model of OMDT was established by dermal TCE sensitization in the presence or absence of C5b-9 inhibitor (sCD59-Cys, 25μg/mouse) and NLRP3 antagonist (MCC950, 10 mg/kg). Kidney histopathology, renal function, expression of inflammatory mediators and the pyroptosis executive protein gasdermin D (GSDMD), and the activation of pyroptosis canonical NLRP3/caspase-1 pathway were examined in the mouse model. Renal tubular damage was observed in TCE-sensitized mice. GSDMD was mainly expressed on renal tubular epithelial cells (RTECs). The caspase-1–dependent canonical pathway of pyroptosis was activated in TCE-induced renal damage. Pharmacological inhibition of C5b-9 could restrain the caspase-1–dependent canonical pathway and rescued the renal tubular damage. Taken together, our results demonstrated that complement C5b-9 plays a central role in TCE-induced immune kidney damage, and the underlying mechanisms involve NLRP3-mediated pyroptosis.
Persistence and Adherence to Biologics in Patients with Psoriasis in Taiwan: A New Biologics User Cohort Study
Authors: Huang Yu-Huei , Tang Chao-Hsiun , Goh Choo Hua , Chang Chia-Li , Qiu Hong , Yang Ya-Wen , Saadoun Carine , Chang Chia-Ling , Liu Yanfang
Published: May 2022

Background: Biologics are used to treat moderate-to-severe psoriasis, and persistence to biologics may reflect clinical effectiveness. Limited information describing how biologics are used in patients with moderate-to-severe psoriasis in Asian countries is available. We conducted a population-based, retrospective, new user cohort study using the National Health Insurance Research Database (NHIRD) in Taiwan to assess treatment persistence and adherence to biologics.

Methods: Adults with a diagnosis of psoriasis between 01 January 2015 and 31 December 2017 were identified in the NHIRD (ICD-9-CM 696.1; ICD-10 L40.0). New users were patients who initiated treatment with etanercept, adalimumab, ustekinumab or secukinumab between 01 January 2015 and 31 December 2017. All eligible patients were followed until 31 December 2018, death or disenrollment. Kaplan-Meier analysis was conducted to estimate persistence of treatment for index biologics. A Cox-proportional hazard regression model was used to compare risks of biologic discontinuation between biologic groups. Adjustments for potential confounding factors (age, gender and Charlson comorbidity index score) were made in the Cox model.

Results: There were 1,397 new biologic users with psoriasis during the study period. The ratio men:women was approximately 4:1. Mean age of patients ranged from 44.6 to 47.7 years across exposure groups. The 1-year/2-years persistence rates were 94.2%/84.9% for ustekinumab, 96.2%/not calculated (due to too few patients at year 2) for secukinumab, 66.0%/29.9% for etanercept, and 59.8%/40.3% for adalimumab. The risk of discontinuation was significantly lower in patients initiating ustekinumab compared with adalimumab (hazard ratio adjusted for age, sex and co-morbidities 0.289, 95%CI 0.247–0.339, p < 0.0001). Drug survival was significantly higher for ustekinumab compared with adalimumab and etanercept (log-rank test p < 0.0001). The proportions of patients with 1-year/2-years medication possession ratios of ≥80% were 95.3%/92.0% for ustekinumab, 98.1%/not calculated for secukinumab, 89.4%/83.1% for etanercept, and 70.8%/59.4% for adalimumab.

Limitations: Clinical improvement and response to treatment data were not available.

Conclusion: There was relatively high persistence amongst biologic users with psoriasis in Taiwan. There is a trend towards greater persistence of ustekinumab compared to other biologics, the magnitude of which depends on the treatment gap used for its calculation. This study provides real-world evidence that may facilitate optimal treatment choice.
Red Blood Cell Membrane-Camouflaged PLGA Nanoparticles Loaded With Basic Fibroblast Growth Factor for Attenuating Sepsis-Induced Cardiac Injury
Authors: Li Xinze , Hong Guangliang , Zhao Guangju , Pei Hui , Qu Jie , Chun Changju , Huang Zhiwei , Lu Zhongqiu
Published: May 2022

Cardiac injury is recognized as a major contributor to septic shock and a major component of the multiple organ dysfunction associated with sepsis. Emerging evidence shows that regulation of the intramyocardial oxidative stress and inflammatory response has a promising prospect. Basic fibroblast growth factor (bFGF) exhibits anti-inflammatory and antioxidant properties. In this study, red blood cell membrane-camouflaged poly (lactide-co-glycolide) nanoparticles were synthesized to deliver bFGF (bFGF-RBC/NP) for sepsis-induced cardiac injury. The in vitro experiments revealed that bFGF-RBC/NP could protect cardiomyocytes from oxidative and inflammatory damage. In addition, the antioxidant and anti-inflammatory properties of bFGF-RBC/NP against cardiac injury were validated using data from in vivo experiments. Collectively, our study used bFGF for the treatment of sepsis-induced cardiac injury and confirmed that bFGF-RBC/NP has therapeutic benefits in the treatment of myocardial dysfunction. This study provides a novel strategy for preventing and treating cardiac injury in sepsis.
Erythropoietin Mitigates Diabetic Nephropathy by Restoring PINK1/Parkin-Mediated Mitophagy
Authors: Yi Xinyao , Yan Wenhui , Guo Tingli , Liu Na , Wang Zhuanzhuan , Shang Jia , Wei Xiaotong , Cui Xin , Sun Yuzhuo , Ren Shuting , Chen Lina
Published: May 2022

Diabetic nephropathy (DN), one of the most detrimental microvascular complications of diabetes, is the leading cause of end-stage renal disease. The pathogenesis of DN is complicated, including hemodynamic changes, inflammatory response, oxidative stress, among others. Recently, many studies have demonstrated that mitophagy, especially PINK1/Parkin-mediated mitophagy, plays an important role in the pathogenesis of DN. Erythropoietin (EPO), a glycoprotein hormone mainly secreted by the kidney, regulates the production of erythrocytes. This research intends to explore the beneficial effects of EPO on DN and investigate related mechanisms. In in vitro experiments, we found that EPO promoted autophagic flux and alleviated mitochondrial dysfunction in terms of mitochondrial fragmentation, elevated mitochondrial ROS as well as the loss of mitochondrial potential, and lowered the apoptosis level in high-glucose-treated mesangial cells. Moreover, EPO increased protein expressions of PINK1 and Parkin, enhanced the co-localization of LC3 with mitochondria, Parkin with mitochondria as well as LC3 with Parkin, and increased the number of GFP-LC3 puncta, resulting in increased level of PINK1/Parkin-mediated mitophagy in mesangial cells. The knockdown of PINK1 abrogated the effect of EPO on mitophagy. In addition, in vivo experiments demonstrated that EPO attenuated renal injury, reduced oxidative stress, and promoted expressions of genes related to PINK1/Parkin-mediated mitophagy in the kidneys of DN mice. In summary, these results suggest that PINK1/Parkin-mediated mitophagy is involved in the development of DN and EPO mitigates DN by restoring PINK1/Parkin-mediated mitophagy.
Trametes robiniophila Murr Sensitizes Gastric Cancer Cells to 5-Fluorouracil by Modulating Tumor Microenvironment
Authors: Xu Jing-Li , Yuan Li , Hu Can , Weng Chun-Yan , Xu Han-Dong , Shi Yun-Fu , Huang Ling , Ying Jie-Er , Xu Zhi-Yuan , Qin Jiang-Jiang , Cheng Xiang-Dong
Published: May 2022

Trametes robiniophila Murr (TRM) is a traditional Chinese medicine which has been used in clinics for enhancing immunity and improving the efficacy of chemotherapy. However, the mechanisms of action of TRM are unknown. In the previous study, we found that the Trametes robiniophila Murr n-butanol extract (TRMBE) comprises the major bioactive components of TRM. In the present study, we aimed to assess the combinational effects of TRMBE and 5-fluorouracil (5-FU) on the treatment of gastric cancer (GC) and explore its mechanism of action. It was found that TRMBE significantly potentiated the anticancer activity of 5-FU and prolonged the survival time of mice bearing Mouse Forestomach Carcinoma (MFC) xenograft tumors. We observed that the combination of TRMBE and 5-FU decreased the risk of liver metastasis in vivo. Furthermore, the combination of TRMBE and 5-FU reduced the levels of immune cytokines IL-6, IL-10, and TGF-β and increased the level of IFN-γ in peripheral blood. This combination therapy also significantly decreased the levels of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and PD-1-positive CD8+ T cells and increased the levels of NK cells in tumor microenvironment (TME). However, TRMBE treatment was unable to enhance the chemosensitivity of GC to 5-FU in vivo after the depletion of CD8+ T and NK cells. Taken together, our results demonstrate that TRMBE can reshape the TME of GC by regulating PMN-MDSCs, CD8+ T cells, and NK cells, therefore improving the therapeutic effects of 5-FU. This study suggests that the combination of TRMBE and 5-FU could enhance immunity and could be a promising approach for GC treatment.
Increase Crop Resilience to Heat Stress Using Omic Strategies
Authors: Zhou Rong , Jiang Fangling , Niu Lifei , Song Xiaoming , Yu Lu , Yang Yuwen , Wu Zhen
Published: May 2022

Varieties of various crops with high resilience are urgently needed to feed the increased population in climate change conditions. Human activities and climate change have led to frequent and strong weather fluctuation, which cause various abiotic stresses to crops. The understanding of crops’ responses to abiotic stresses in different aspects including genes, RNAs, proteins, metabolites, and phenotypes can facilitate crop breeding. Using multi-omics methods, mainly genomics, transcriptomics, proteomics, metabolomics, and phenomics, to study crops’ responses to abiotic stresses will generate a better, deeper, and more comprehensive understanding. More importantly, multi-omics can provide multiple layers of information on biological data to understand plant biology, which will open windows for new opportunities to improve crop resilience and tolerance. However, the opportunities and challenges coexist. Interpretation of the multidimensional data from multi-omics and translation of the data into biological meaningful context remained a challenge. More reasonable experimental designs starting from sowing seed, cultivating the plant, and collecting and extracting samples were necessary for a multi-omics study as the first step. The normalization, transformation, and scaling of single-omics data should consider the integration of multi-omics. This review reports the current study of crops at abiotic stresses in particular heat stress using omics, which will help to accelerate crop improvement to better tolerate and adapt to climate change.
Ground-Level Pruning at Right Time Improves Flower Yield of Old Plantation of Rosa damascena Without Compromising the Quality of Essential Oil
Authors: Shivani  , Mahajan Mitali , Thakur Babit Kumar , Pal Probir Kumar
Published: May 2022

The essential oil of Rosa damascena is extensively used as a key natural ingredient in the perfume and cosmetic industries. However, the productivity and quality of rose oil are a big concern from the old plantation. It is hypothesized that rejuvenation of old rose plantations through ground-level pruning at right time could improve the yield of flowers and the quality of essential oil. Consequently, a field trial was led-out with 10 treatment conditions encompassing two pruning systems (ground-level pruning and ground-level pruning followed by top pruning at the end of December) and five different months of ground-level pruning (June–October) to understand the best pruning practices. In this experiment, the flower yield ranged from 18.32 to 62.40 q ha−1, and oil content varied from 0.035 to 0.049% under different pruning systems and months of pruning. Ground-level pruned plants, irrespective of the month, registered statistically (p ≤ 0.05) more flower yield (618.62 and 473.29 g bush−1) compared with ground-level pruning followed by top pruned plants in both seasons. The average across the pruning system, ground-level pruning in October registered statistically (p ≤ 0.05) greater yield of flowers (709.10 and 605.13 g bush−1) compared with the ground-level pruning from June to August. Despite significant variations in flower yield among the treatments, the percentage share of the major compounds particularly β-citronellol+nerol and geraniol in the essential oil were not affected (p ≥ 0.05) by the pruning month and pruning system. Thus, the finding suggests that the production from the old plantation of R. damascena can be improved by ground-level pruning during October under mild-temperate conditions.
Rhythmic Relating: Bidirectional Support for Social Timing in Autism Therapies
Authors: Daniel Stuart , Wimpory Dawn , Delafield-Butt Jonathan T. , Malloch Stephen , Holck Ulla , Geretsegger Monika , Tortora Suzi , Osborne Nigel , Schögler Benjaman , Koch Sabine , Elias-Masiques Judit , Howorth Marie-Claire , Dunbar Penelope , Swan Karrie , Rochat Magali J. , Schlochtermeier Robin , Forster Katharine , Amos Pat
Published: May 2022

We proposeRhythmic Relatingfor autism: a system of supports for friends, therapists, parents, and educators; a system which aims to augment bidirectional communication and complement existing therapeutic approaches. We begin by summarizing the developmental significance ofsocial timingand thesocial-motor-synchronychallenges observed in early autism. Meta-analyses conclude the early primacy of such challenges, yet cite the lack of focused therapies. We identify core relational parameters in support of social-motor-synchrony and systematize these using thecommunicative musicalityconstructs:pulse;quality; andnarrative.Rhythmic Relatingaims to augment the clarity, contiguity, and pulse-beat of spontaneous behavior by recruiting rhythmic supports (cues, accents, turbulence) and relatable vitality; facilitating the predictive flow and just-ahead-in-time planning needed for good-enough social timing. From here, we describe possibilities for playful therapeutic interaction, small-step co-regulation, and layered sensorimotor integration. Lastly, we include several clinical case examples demonstrating the use ofRhythmic Relatingwithin four different therapeutic approaches (Dance Movement Therapy, Improvisational Music Therapy, Play Therapy, and Musical Interaction Therapy). These clinical case examples are introduced here and several more are included in theSupplementary Material(Examples of Rhythmic Relating in Practice). A suite of pilot intervention studies is proposed to assess the efficacy of combiningRhythmic Relatingwith different therapeutic approaches in playful work with individuals with autism. Further experimental hypotheses are outlined, designed to clarify the significance of certain key features of theRhythmic Relatingapproach.
The Chain-Mediation Pathway of Social Avoidance to Depression in College Students Is Regulated by Self-Esteem
Authors: Yuan Ye , Jiang Suhua , Wen Xi , Han Zhong , Wu Daili , Wang Xuanping , Ye Tingyang , Hu Yimin , Jeong Jaesik , Xiang Min
Published: May 2022

Objective

Here, we investigated the relationship between social avoidance and depression in college students, explored the mediating roles of loneliness and trust, and the regulatory role of self-esteem, to provide a theoretical intervention approach based on internal mechanisms.

Methods

Using a simple random overall sampling method, 1,021 college students were investigated using self-rating depression, social avoidance and distress, loneliness, interpersonal trust and self-esteem scales.

Results

There was a significant positive correlation between social avoidance and depression. Loneliness and interpersonal trust played chain-mediating roles between social avoidance and depression. The influence of social avoidance on interpersonal trust was regulated by self-esteem. Specifically, the social avoidance level of the low self-esteem group was more likely to be affected by interpersonal trust issues.

Conclusion

Social avoidance not only directly affects college students’ depression, it also has indirect effects through interpersonal trust and loneliness. Thus, interpersonal trust and loneliness have chain-mediating effects between social avoidance and depression in college students, and self-esteem regulates the mediation process.
Safe-Sex Behavioral Intention of Chinese College Students: Examining the Effect of Sexual Knowledge Using the Theory of Planned Behavior
Authors: Wang Xin , Jin Yuanqing , Tian Mengqin , Zhuo Qinzi , Lin Chien-Liang , Hu Pengfei , Wang Ting
Published: May 2022

Numerous contemporary studies have examined safe sexual behavior among college students. In China, families are reluctant to discuss sexual behavior, thus understanding and exploring the sexual knowledge of college students and the promotion of safe sexual behavior is essential. On the basis of the theory of planned behavior (TPB), a cognitive behavioral theory that is widely used to predict human social behavior, we conducted an in-depth investigation of the factors influencing the sexual behavioral intentions of Chinese college students. We referenced the relevant literature to develop a TPB-based model for analyzing differences in sexual knowledge. Our statistical analysis revealed the following: (1) subjective norms and behavior control are key variables that influence the safe sexual behavior of college students; (2) attitudes and safe-sex behavioral intentions are influential in groups with extensive sexual knowledge; (3) behavioral control and subjective norms influence the differences in the comparative sexual knowledge of students. On the basis of the present results, we propose research recommendations and directions for the development of sex education in China.